Advances in One-Pot Synthesis through Borrowing Hydrogen

Review Cite This: Chem. Rev. 2018, 118, 1410−1459

pubs.acs.org/CR

Advances in One-Pot Synthesis through Borrowing Hydrogen Catalysis Avelino Corma,* Javier Navas, and Maria J. Sabater* Instituto de Tecnología Química, Universitat Politècnica de València-Consejo Superior de Investigaciones Científicas, Avenida Los Naranjos s/n, 46022 Valencia, Spain ABSTRACT: The borrowing hydrogen (BH) principle, also called hydrogen autotransfer, is a powerful approach which combines transfer hydrogenation (avoiding the direct use of molecular hydrogen) with one or more intermediate reactions to synthesize more complex molecules without the need for tedious separation or isolation processes. The strategy which usually relies on three steps, (i) dehydrogenation, (ii) intermediate reaction, and (iii) hydrogenation, is an excellent and well-recognized process from the synthetic, economic, and environmental point of view. In this context, the objective of the present review is to give a global overview on the topic starting from those contributions published prior to the emergence of the BH concept to the most recent and current research under the term of BH catalysis. Two main subareas of the topic (homogeneous and heterogeneous catalysis) have been identified, from which three subheadings based on the source of the electrophile (alkanes, alcohols, and amines) have been considered. Then the type of bond being formed (carbon−carbon and carbon heteroatom) has been taken into account to end-up with the intermediate reaction working in tandem with the metal-catalyzed hydrogenation/dehydrogenation step. The review has been completed with the more recent advances in asymmetric catalysis using the BH strategy.

CONTENTS 1. Introduction 2. Borrowing Hydrogen Methodology in Homogeneous Catalysis 2.1. Activation of Alkanes 2.1.1. Formation of C−C Bonds 2.1.2. Formation of C−N Bonds 2.2. Activation of Alcohols 2.2.1. Formation of C−C Bonds 2.2.2. Formation of C−N Bonds 2.3. Activation of Amines 2.3.1. Formation of C−C Bonds 2.3.2. Formation of C−N Bonds 2.4. Asymmetric Borrowing Hydrogen Catalysis 2.4.1. Activation of C−O Bonds (Alcohols) 3. Borrowing Hydrogen Methodology in Heterogeneous Catalysts 3.1. Activation of Alkanes 3.1.1. Formation of C−C Bonds 3.2. Activation of Alcohols 3.2.1. Formation of C−C Bonds 3.2.2. Formation of C−N Bonds 3.2.3. Formation of C−S Bonds 3.3. Activation of Amines 3.3.1. Formation of C−N Bonds 4. Conclusions and Future Trends Author Information Corresponding Authors ORCID © 2018 American Chemical Society

Notes Biographies Acknowledgments List of Abbreviations References

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1. INTRODUCTION The borrowing hydrogen (BH) principle also called hydrogen auto-transfer is a powerful strategy which combines transfer hydrogenation (avoiding the direct use of molecular hydrogen) with one or more intermediate reactions to form more complex molecules without the need for tedious separation or isolation processes. The key to this concept is that the hydrogen from a donor molecule will be stored by a catalytic metal fragment to be released in a final hydrogenation step, hence the reaction name. Following the above, the development of catalytic systems in borrowing hydrogen catalysis involves metal complexes or stabilized metal particles in which H2 dissociation and recombination is simple, preferably without requiring severe reaction conditions. Unfortunately most of the metal hydrides that may form during hydrogen activation processes are too stable to easily give back the activated hydrogen, being therefore inactive for the BH methodology.1,2 For example, ruthenium (Ru), 3,4 iridium (Ir),5 and rhodium (Rh) 6

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Received: June 14, 2017 Published: January 10, 2018 1410

DOI: 10.1021/acs.chemrev.7b00340 Chem. Rev. 2018, 118, 1410−1459

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homogeneous transition metal complexes in the search for more active catalysts. Nonetheless it is well-known that homogeneous metal catalysts generally require the use of additives (ligands, acids, or bases), a fact that decreases the atom economy, whereas a wide variety of heterogeneous catalysts can be active under additive free conditions, also being true within the context of borrowing hydrogen catalysis. Another key concept when using solid catalysts for borrowing hydrogen reactions is the possibility to prepare multifunctional catalysts. This has been achieved by preparing metal-loaded acidic and/or basic oxides, in which one of the acidic or basic sites selectively catalyzes the intermediate reaction, whereas the metallic component will catalyze both the dehydrogenation and hydrogenation steps.9 Due to its lack of a formal name, the BH concept has been passed by as it is extremely difficult to encounter, especially in early research. For this reason, the present report aims to rectify this situation for future or existing research by giving a global overview on the topic starting with those contributions published prior to the emergence of the BH concept to the most up-to-date research under the term of BH catalysis. In this sense, it is important to note that most related review articles collect developments and/or improvements in the field albeit giving a partial overview on the topic.9−20 In this regard, here we have also included other aspects that have not been sufficiently emphasized so far within the field of BH catalysis, such as alkane metathesis, a challenging reaction that has not been included in any of the most recent reviews on the topic. Thus, first, we have identified the main two subareas of the topic (homogeneous and heterogeneous catalysis), from which we have considered three main subheadings based on the source of the electrophile (alkanes, alcohols, and amines). Then the type of bond being formed (carbon−carbon, carbon heteroatom) has been taken into account to end-up with the intermediate reaction working in tandem with the metalcatalyzed hydrogenation/dehydrogenation step. This classification is very comprehensive and whenever possible we will try to illustrate each of these sections with recent examples of bibliography. The review has been completed with the more recent advances in asymmetric catalysis using the BH strategy. So far the number of publications on this subject is scarce, as a result of the challenging conditions needed to perform enantioselective transformations within the context of borrowing hydrogen catalysis. Nonetheless, given that this issue has been successfully addressed with different homogeneous catalysts (e.g., by decreasing reaction temperatures below 40 °C), a representative number of reports on the enantioselective variant of BH will also be included here.13 Nonetheless, BH methodology as a tool for racemisation as well as dynamic kinetic resolution (DKR) of different substrates (e.g., secondary alcohols) is a topic that is out of the scope of this literature review.

complexes, among others, are typical homogeneous complexes that have been reported for these reactions. The borrowing hydrogen strategy begins with a metalcatalyzed dehydrogenation, by virtue of which a usually less reactive donor molecule is temporarily converted into a more reactive substrate (e.g., an alkane transforms into an alkene, an alcohol into an aldehyde, or a ketone and an amine into an imine). The more activated intermediate can undergo further transformations to give an unsaturated compound that will be reduced with the intervention of the metal hydrides generated during the first dehydrogenation step. A basic scheme of this concept is depicted in Scheme 1. Scheme 1. Basic Scheme of the BH Methodology

In accordance with Scheme 1, the strategy typically relies on three steps: (i) dehydrogenation, (ii) intermediate reaction, and (iii) hydrogenation. Taking into account that the intermediate reaction step is a common organic reaction involving the dehydrogenated substrate (e.g., an aldehyde), the participation of the metal at this point is not absolutely essential, although this assumption may not necessarily hold since an electrophilic metal component of the catalyst can, for instance, increase the electrophilic nature of the CO bond and thus enhance its reactivity. An interesting feature of this method is that the hydrogenation step is usually thermodynamically favored, and this shifts the global process completely to the products, resulting in a very low E-factor. In essence, the irreversibility of the third step in Scheme 1 drives the first dehydrogenation step to nearcompletion. In this case, the same function can catalyze the dehydrogenation of the reactant and the hydrogenation of the intermediate product with the metal hydrides produced in the first step. It appears then that borrowing hydrogen catalysis is an excellent process from the synthetic, economic, and environmental point of view. Therefore, not surprisingly, the BH reactions have received much attention in the past few years. In this respect, it is necessary to indicate that there are few examples that despite not strictly following the basic reaction sequence detailed in the Scheme 1 (dehydrogenation/ intermediate reaction/hydrogenacion), they fulfill the philosophy of the BH strategy in the sense that the dehydrogenation product is not a waste any more.7,8 As an example during the synthesis of pyrroles from 1,4-alkynediols7 catalyzed by different ruthenium complexes, the hydrogenation reaction will occur immediately after the dehydrogenation step (and not at the end) on the resulting 1,4-alkynediketone followed by Nheterocyclization.7 Although early studies on heterogeneous systems reported more than three decades ago are the origin of this strategy, the real development of BH catalysis was paralleled by the design of

2. BORROWING HYDROGEN METHODOLOGY IN HOMOGENEOUS CATALYSIS 2.1. Activation of Alkanes

The C−C bond is one of the strongest, more stable bonds, and for this reason it is of high importance to activate such covalent sigma link. One way to do this is by dehydrogenation to produce an olefin which may in principle undergo transformations such as metathesis as a route to longer alkanes. 1411


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decreased at temperatures higher than 125 °C surely due to the instability of the catalyst under the experimental conditions, albeit interestingly some of these catalysts could be synthesized in situ.29 For example, the catalytic results collected in Table 129 were obtained by using the iridium catalyst 1 together with different

Obviously, alkane dehydrogenation integrated within the context of borrowing hydrogen catalysis can be an efficient and powerful route to activate alkanes. 2.1.1. Formation of C−C Bonds. 2.1.1.1. Olefin Metathesis. Metathesis of alkenes working in tandem with dehydrogenation/hydrogenation reactions is a powerful BH strategy to form new alkanes known as alkane metathesis. Globally, alkane metathesis is a chemical reaction in which alkanes are rearranged to give longer alkanes as final products. It is similar to olefin metathesis,21−23 except that olefin metathesis cleaves and forms new carbon−carbon double bonds, while alkane metathesis operates on carbon−carbon single bonds. Thus, alkane metathesis has been conceived on the bases of a tandem operational combination of alkane dehydrogenation/hydrogenation and olefin metathesis reactions24 as depicted in Scheme 2.

Table 1. Concentration of Final Products When Reacting Iridium Catalyst 1 (10 mM) and Diverse Mo and W Alkylidene Complexes (16 mM) at 125 °C in n-Octane after 4 Daysa

Scheme 2. Borrowing Hydrogen and Olefin Metathesis Working in Tandem

One of the first homogeneous catalytic systems for converting a specific alkane into a higher homologue by means of BH methodology consisted of combining one iridium complex (e.g., complexes 1−3, Figure 1) as dehydrogenation/

Figure 1. Structure of complexes 1−4 designed by Brookhart and Goldman for alkane metathesis reactions. Adapted with permission from ref 26. Copyright 2006 AAAS.

hydrogenation catalyst25 and the Schroks molybdenium imido olefin catalyst 4, being reported in 2006 by Goldman et al.26,27. The process was able to transform n-hexane into a range of C12 to C15 n-alkanes. In Figure 1, the structure of catalysts 1−4 reported by Brookhart and Goldman for performing the dehydrogenation/ metathesis/hydrogenation step is shown. Other bisphosphine- and biphosphinite-based iridium complexes [(tBu4PCP)Ir and (tBu4POCOP)Ir] combined with a Mo complex (MoF12) were also able to catalyze transfer hydrogenation and olefin-metathesis reactions under alkane metathesis conditions.28 In this context, and in search for an efficient alkane metathesis system, an improved homogeneous dual catalytic system was developed by Schrock et al.29 In this case, over 40 molybdenum and tungsten catalysts were tested in combination with an Ir-pincer-based complex as dehydrogenation/hydrogenation catalyst. With this dual system, the product yield

entry

catalyst

total product (mM)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Mo(NAr)(CHR)(pyr)2 Mo(NAd)(CHR)(pyr)2 W(NAr)(CHR)[OCMe(C6F5)2]2 Mo(NAr)(CHR)[OCMe(C6F5)2]2 Mo(NArCF3)(CHR)[OCMe(CF3)2]2 W(NAr)(CHR)(pyr)2 Mo(NAr)(CHR)(CH2−tBu)2 W(NAr)(CHR)(CH2−tBu)2 Mo(NArCF3)(CHR)(pyr)2 W(NAr)(CHR)(OAr)2 Mo(NAr)(CHR)(O-1-PhCy)(pyr) Mo(NAr)(CHR)(OTBS)2 Mo(NAr)(CHR)(BIPHEN) Mo(NAr)(CHR)[OC(CF3)3]2 Mo(NAd)(CHR)[OCMe(CF3)2)2 Mo(NAr)(CHR)(BINAPm‑CF3) W(NAr″)(CHR)[OCMe(CF3)2]2 Mo(NAr)(CHR)[OSi(O-tBu)3](pyr) Mo(NAr)(CHR)(BINAP-TBS)2 Mo(NAr)(CHR)[OCMe(CF3)2](pyr) Mo(NAr)(CHR)(OAr)2 Mo(NAr)(CHR)(OCMe2CF3)2 Mo(NAr)(CHR)(OAr)(pyr) W(NAr)(CHR)(OAr)(pyr) W(NAr)(CHR)(OCMe2CF3)2 Mo(NAr)(CHR)[OCMe(CF3)2]2 W(NAr)(CHR)[OC(CF3)3](pyr) W(NAr)(CHR)(BINAP-TBS)2 W(NAr)(CHR)[OCMe(CF3)2](pyr) Mo(NAr)(CHR)(OSiPh3)(pyr) W(NAr)(CHR)[OC(CF3)3]2b Mo(NAr)(CHR)(OSiPh3)2 W(NAr)(CHR)[OCMe(CF3)2]2 W(NAr)(C3H6)[OC(CF3)3]2 W(NAr′)(CHR)[OCMe(CF3)2]2 W(NAr)(CHR)[OC(CF3)3]2c W(NAr)(CHR)(OSiPh3)(pyr) W(NAr)(CHR)[OC(CF3)3]2 W(NAr)(CHR)(OSiPh3)2 W(NAr)(CHR)[OC(CF3)3]2d

15 25 25 33 41 81 89 122 130 141 152, 162 159 184 242 334, 358 359 419 480 486, 593 746, 794 759 808 963, 1120 1040 1200 1430, 1640 1550 1580 1670 1800 1890 1970 2030 2210 2230 2310 2380 2760 3380 3015

a

Reproduced from ref 29. Copyright 2009 American Chemical Society. Legend: CHRCHCMe2Ph; Ar = 2,6-diisopropylphenyl; Ar′ = 2,6-dimethylphenyl; Ar″ = 2,6-dichlorophenyl; ArCF3 = 2(trifluoromethyl)phenyl; Ad = 1-adamantyl; pyr = 2,5-dimethylpyrrolide; BIPHEN = 3,3′-di-tert-butyl-5,5′,6,6′-tetramethyl-1,1′-biphenyl2,2′-diolate; BINAPm‑CF3 = 3,3′-bis(3,5-bis(trifluoromethyl)phenylBINOL; BINAP-TBS = 2′-(tert-butyldimethylsilyl)oxy)-1,1′-binaphtyl-2-olate. Repeated run values are given in some instances. bReaction at 175 °C. cReaction at 150 °C. dReaction at 100 °C, maximizing after 14 days. 1412


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Scheme 3. Diarylamines (7) Formation from Nitroarenes (5) and Cyclohexanone Derivatives (6) on Pd Catalysts Using Borrowing Hydrogen Methodsa

a

Reproduced from ref 51. Copyright 2012 American Chemical Society.

Scheme 4. Proposed Reaction Pathwaya

a


context than Mo catalysts.34−36 Another remarkable feature regarding the use of different metals in these processes is the involvement of Ru catalysts just in classical olefin metathesis processes and not in BH methodology.37−39 This fact is surprising if we take into account that Ru complexes can be a catalyst of choice in those cases where Mo complexes are sensitive to water, molecular oxygen, and certain protic functionalities. In any case, the remaining challenges, both in classical metathesis processes and BH methodology, will include increasing the TON by slowing or preventing the decomposition of the metathesis catalyst. In this regard, it is interesting to indicate that diverse scandium, yttrium, and lutetium-based complexes for methane metathesis reaction have also been studied.40 The complexes were formed by ansa-indenyl ligands with different methylation degrees. In this case, the effect of the methylene-bridged ansa ligand on the complex geometries and activation enthalpies was quantified. Thus, it appears that so far homogeneous catalysts have not given satisfactory turnover numbers when applied in alkane metathesis processes due to various challenges that still remain to be solved. In particular, the activation of methane in order to synthesize longer alkanes in the range of high quality diesel and jet fuel; a fact that with certainty would help to solve current and future energy problems. 2.1.2. Formation of C−N Bonds. Amines are important compounds for the chemical industry as intermediate products in the preparation of dyes, polymers, as well as for the synthesis of new pharmaceuticals, food additives, etc.41,42 The amine-type functionality is also included in compounds with biological or pharmacological activity (e.g., nucleotides, amino acids, alkaloids, etc.).

molybdenum and tungsten complexes. The n-octane metathesis was used as a model reaction, giving a final product concentration that varied from 15 to 3380 mM. The catalytic experiments were carried out by using a 10 mM solution of 1 together with the W or Mo catalyst (16 mM) in n-octane as solvent with mesitylene (28 mM) as the internal standard. Probably one of the most important conclusions that can be drawn from Table 1 is the higher performance of W catalysts among all the catalysts studied. In fact, at least 13 W-based catalysts were identified as the most active ones. As an example, the highest concentration of n-octane metathesis product (3380 mM) was obtained with catalyst W(NAr)(CHR)(OSiPh3)2 (entry 39, Table 1), a catalytic system that contains W and two triphenylsiloxide ligands (one of the most typical auxiliary ligands in this type of chemistry).29 Such marked differences between these two series of Mo and W complexes can be related to a greater reluctance of tungsten compounds to be reduced (either by rearrangement of different metallacyclobutane intermediates or by decomposition of the respective alkylidene complexes). In fact, there are several examples of tungstacyclobutane complexes but the parent molybdacyclobutanes have only been observed spectroscopically.30−33 Another interesting conclusion is that the electrophilicity of the metal will play an important role in catalysis. Indeed as the electro-withdrawing effect of the alkoxide directly bound to W increases from trifluoro- to nonafluoro- tert-butoxide, the concentration of the metathesis product also increases (from 1200 to 2760 mM), though this trend is not held for the series of Mo complexes (entries 25, 38; Table 1). It is interesting to note that similar high oxidation state Mo and W complexes have also been applied in classical olefin metathesis processes (organic synthesis and polymer chemistry), being the W complexes rather less explored in this 1413


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will afford nucleophilic alkoxides, albeit the incorporation of an acid will give rise to electrophilic species.52,53 Nonetheless, alcohols are generally poor electrophiles for alkylation reactions, requiring activation of the hydroxyl group into a suitable leaving group in order to facilitate the nucleophilic substitution.54 A different approach to activate alcohols involves the removal of hydrogen from the alcohol to form an aldehyde, something that is usually carried out by dehydrogenation reactions in hydrogen autotransfer processes. In this case, the temporary transformation of alcohols into aldehydes or ketones has been exploited, for instance, for forming alkenes or imines (or enamines) followed by subsequent reduction to a C−C or a C−N bond.10,11,14,16,19,55−57 The activation of alcohols in hydrogen autotransfer has also been extensively studied in recent years in the form of a varied combination of BH reactions. In this sense, few references are out of specific bibliography reviews that have appeared on the subject in the last years. Nevertheless, we will try to illustrate this section with examples that have not been cited in previous specific revisions (either for forming C−C or C−N bonds), but when this is not possible, we will describe just significant examples ensuring that this Review does not lose its main structure. 2.2.1. Formation of C−C Bonds. There are numerous examples in which carbonyl compounds formed originally from an alcohol are involved in ulterior C−C forming reactions by virtue of borrowing hydrogen methods to give the corresponding alkenes. Then the resulting olefins will be hydrogenated in situ to afford saturated alkanes through a net alkylation process.11,17,18 2.2.1.1. Aldol Condensation. Aldol condensation is a wellknown reaction in classic organic synthesis when it comes to the formation of C−C bonds by reacting aldehydes and/or ketones. In this respect, two different mechanisms have traditionally been established depending on the acid or basic nature of the catalyst.58,59 At this point, it is possible to integrate this reaction within the BH strategy allowing access to more complex structures starting from simple alcohols. In this case, the hydroxylic compound would dehydrogenate into the corresponding aldehyde or ketone hence initiating the global reaction (Scheme 5). Once the corresponding carbonyl compound is formed, the aldol condensation takes place yielding the corresponding α,β-unsaturated compound through

At this point, besides the traditional alkylation methods to get amines,43 the development of improved catalytic processes for the synthesis of amines is still an active topic of research. For example, during the past decade, various catalytic aminations, such as palladium- and copper-catalyzed aminations of aryl halides,44,45 hydroaminations,46,47 hydroaminomethylations,48 or reductive aminations49,50 have received increased attention due to the high levels of conversion and yields of the corresponding amines. However, a re-examination of the above processes from an environmental point of view (utilization of hazardous chemicals and solvents) shows that BH processes are definitely superior. Therefore, unsurprisingly, certain industries are now investing and trying to implement this BH strategy for manufacturing amines. Thus, within the context of forming amines through catalysis by borrowing hydrogen, the activation of C−C bonds (upon dehydrogenation) has been combined with ulterior successive reactions (see reported results below). 2.1.2.1. Condensation (N-Arylation). There is only an example of reaction initiated by alkane activation within the context of BH catalysis affording N-arylations which has been included in a recent literature review.10 Since there has not been further examples on this issue, this reference will be described below so it does not pass unnoticed by the reader. N-Arylation reactions involve the participation of cyclohexanone derivatives (acting simultaneously as hydrogen donors and aryl sources) with nitroarenes behaving as a source of nitrogen for forming diarylamines (Scheme 3).51 Mechanistically, nitroarenes (5) are reduced to amines (9) using hydrogen generated from an initial cyclohexanone derivative (6) dehydrogenation step (Scheme 4).51 Then, the resulting cyclic enone (8) will react with the aromatic amine 9 through a condensation reaction for forming initially an imine intermediate (10) that will be transformed into a diarylamine (7) through BH catalysis (Scheme 4). All the reactions involved (nitro reduction, cyclohexanone dehydrogenation, imine formation, and dehydrogenation) were carried out in a cascade mode, and a variety of groups (alkyl, alkoxy, ester, as well as an acetyl function) were well-tolerated. To summarize this section, alkane metathesis is one of the most promising reactions involving the activation of C−C bonds due to its enormous potential in transforming both renewable and fossil feedstocks to alkanes (in particular in the range of high quality diesel and jet fuel). However, despite great progress in the area of alkane metathesis there are still problems to overcome. Among them, the dehydrogenation catalysts which give acceptable rates only at temperatures at which the alkylidene-based olefin-metathesis catalysts tend to decompose. Thus, there is a real need to develop olefin metathesis catalysts that are more robust at higher temperatures, together with more regioselective dehydrogenation catalysts able to operate at moderated temperatures. In general, processes in which alkanes are activated should be exploited not only for forming carbon−carbon bonds but also for forming carbon-heteroatom bonds. This will result in new and unexpected reaction pathways that will contribute to the expansion of the number of transformations in the context of hydrogen autotransfer processes. At the moment, this possibility has hardly been explored.

Scheme 5. Schematic Representation of the BH Methodology Involving an Aldol Condensation as the Intermediate Reaction

2.2. Activation of Alcohols

The reactivity of alcohols expands enormously when we consider their activation. For instance, the addition of a base 1414


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reaction of alkynes within the context of BH methodology as depicted in Scheme 6.74 In this case, in the presence of (iPr)AuCl (15), silver triflate (AgOTf), and water, a series of alkynes (11) were first hydrated to give the corresponding methyl ketones (12), which in turn were α-alkylated by adding the iridium complex [Cp*IrCl2]2 (16), KOtBu, and alcohols to the reaction mixture.74 This reaction is highly attractive due to the availability of starting materials, the undeniable atom efficiency, the good to outstanding yields, and the low consumption of chemicals and energy. Rhodium catalysts, though they are less frequently applied in borrowing hydrogen methods than ruthenium or iridium, have also catalyzed the α-alkylation of ketones (13) using methanol as well as other primary alcohols as methylating agents.75,76 The same statement is applied to iron, which is considered as a valuable alternative to the use of precious transition metals in terms of sustainability and economy. For this reason, in the past decade the use of iron catalysts have increasingly been applied in C−C bond forming reactions. An interesting example within the context of BH strategies has been reported on ironcatalyzed α-alkylation of ketones with primary alcohols in the presence of a Knölberg-type iron complex (19) (Scheme 7).77 Knölberg-type complexes are stable precursors that have been successfully used in hydrogenations and hydrogen transfer reactions as well as for selective oxidations of alcohols.14 In this case, the iron complex catalyzed the α-alkylation of ketones in the presence of catalytic amounts a base. Furthermore, an optimized system (22/PPh3) catalyzed the Friedlander annulation reaction starting from an amino benzyl alcohol derivative (13b) and a ketone (20) to give quinolones (21) (Scheme 8).77 In general the low stability of the 2-aminobenzaldehyde compound is one of the challenges of this reaction. But under BH conditions the use of the more stable 2-aminobenzyl alcohol (13b) in the presence of catalytic amounts of tBuOK resulted in a truly advantageous alternative to carry out this reaction. Other alternatives concerning the use of alcohols as starting reagents in BH processes involve the use of primary and secondary alcohols to yield the corresponding β-alkylated products (Figure 2). As in the previous case, ruthenium and iridium catalysts have been again extensively applied in these BH processes.78−86 For example, a ruthenium compound containing a triazoledicarbene ligand was prepared and characterized as a tetraruthenium species 25 showing an

an enol or enolate intermediate. Finally, metal hydrides formed in the first step would reduce the unsaturated compound to the corresponding alcohol (Scheme 5). Given that either one or both reactants can be alcohols, different combinations based on the nature of the starting reactants can be distinguished a priori in order to address a variety of BH reactions (Figure 2).

Figure 2. Schematic representation of the different approaches for the indirect aldol condensation through the BH strategy.

Briefly, three different reaction routes can take place in hydrogen autotransfer processes involving the aldolic reaction depending on the starting reagent (Figure 2): (a) α-alkylation of carbonyl compounds with alcohols, (b) β-alkylation of secondary alcohols to give β-alkylated alcohols or β−alkylated ketones, and (c) β-alkylation of primary alcohols with primary alcohols to yield β-alkylated alcohols. These possibilities have been addressed in relatively recent studies and a collection of representative catalysts which were successfully applied in these C−C forming reactions have been included in diverse reviews.11,16−18 Among them, the use of ruthenium and iridium complexes must be highlighted. For example, ruthenium-based complexes have been widely applied for the α-alkylation of ketones60−64 or amides65 with primary alcohols (Figure 2). Similarly, iridium complexes have attracted much attention in α-alkylations starting from ketones66−71 and esters.72,73 In this context, one interesting contribution which appeared recently, introduced the possibility of performing an intensive process consisting of combining the BH-aldol condensation with another different reaction. Basically, α-alkylation of ketones (14) could be integrated together with the hydration

Scheme 6. Strategy for the Synthesis of α-Alkylated Ketones (14) Starting from Alkynes (11) and Alcohols (12)a

a

Adapted with permission from ref 74. Copyright 2014 Wiley-VCH. 1415


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Scheme 7. α-Alkylation of Acetophenone with Benzyl Alcohol Catalyzed by a Knölberg Iron Complex (19)a

a

Adapted with permission from ref 77. Copyright 2015 Wiley-VCH.

Scheme 8. Example of Friedlander Annulation Reaction Using Catalytic Amounts of tBuOK and the Iron Complex 22a

a


excellent catalytic activity in the β-alkylation of secondary alcohols with primary alcohols (Scheme 9).78

It is important to emphasize that both complexes were active regardless of whether the alcohols were aliphatic or aromatic. A second recent example on Ru(III) catalyzed β-alkylation of secondary alcohols with primary alcohols was reported by Wang et al. In this case, the catalyst was prepared by mixing RuCl3 and the ligand 28 in refluxing ethanol to give the catalyst 29 (Scheme 11).85 The complex was characterized by HRMS, elemental analysis, and IR. Indeed the HRMS analysis showed a peak assigned to the fragment ([M − Cl]+), whereas the IR spectrum showed a stretching vibration that shifted from 1580 cm−1 from the original ligand to 1609 cm−1 due to the coordination effect with the metal cation. The complex was active in a wide variety of examples going from primary to secondary alcohols. Scheme 1285 shows selected examples obtained with this catalytic system to show the generality of the reaction. A different representative example for the β-alkylation involved the participation of two different Ru complexes (Figure 2). In this context, Beller et al. reported the successful combination of two ruthenium catalysts [Ru-MACHO (30) and Shvo’s catalyst (31)] for the selective cross-coupling of methanol and 2-arylethanols (Figure 3).88 The key point to this contribution was the access to products that alternatively have to be prepared by hydroformylationreduction sequences (Scheme 13).88 Besides this, other obvious advantages to the present straightforward approach are the avoidance of toxic CO and extra hydrogen, as well as the need for high pressure equipment. Mechanistically, the combination of these two different ruthenium catalysts accounted for the occurrence of two different dehydrogenation reactions, a selective aldol reaction, subsequent dehydration, and a final hydrogenation step (Scheme 13). The use of iridium complexes has also been a recurrent issue in β-alkylations of alcohols under BH catalysis. For example, recent approaches89−91 for forming functionalized ketones have

Scheme 9. Schematic Preparation of Dinuclear (24) and Tetranuclear Ruthenium Complexes (25) Coordinated to Triazolediylidene Ligandsa

a


In principle, the triazolediylidene ligand had been previously employed in the synthesis of dinuclear homoheterometallic species of Rh and Ir,87 where it was shown that the connection of two catalytically active metal fragments provided a synergistic effect that accounted for a high catalytic performance. On this basis, the corresponding ruthenium analogues were prepared being applied in the β-alkylation of secondary alcohols with primary alcohols in a one-pot process under BH conditions (Scheme 10).78 1416


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Scheme 10. β-Alkylation of Secondary Alcohols with Primary Alcohols Catalyzed by Dinuclear and Tetranuclear Ruthenium Complexes 24 and 25a

a


Scheme 11. Schematic Preparation of Ru(III) Complex 29 Obtained by Wanga

a


Figure 3. Structure of ruthenium catalysts Ru-MACHO 30 and Shvo’s catalyst 31. Adapted with permission from ref 88. Copyright 2014 Royal Society of Chemistry.

been described through the cross-coupling of primary and secondary alcohols with neutral (32−35) and cationic iridium (36−39) catalysts (Scheme 14).91

In this particular case, the iridium(I) complexes containing hemilabile O- and N-donor-functionalized ligands were synthesized by means of deprotonation of functionalized

Scheme 12. Scope of primary and secondary alcohols obtained with Ru(III) complex 29. Reproduced from ref 85. Copyright 2016 American Chemical Society

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Scheme 13. Plausible Reaction Scheme for the β-Alkylation Involving Two Primary Alcoholsa

H2O, which has also been used as a catalyst for forming new branched alcohols starting from primary and secondary alcohols,95 albeit with a controversial reaction mechanism. The reference which has been included in a specific review on C-alkylation of ketones through BH methodology11 brings with it reasonable doubt which arises due to the acceleration of the reaction under air atmosphere. In this respect, the authors point to a plausible transfer hydrogenation via a six-membered cyclic Meerwein-Pondorf-Verley type transition state instead of a BH strategy, although none of the two mechanisms can be discarded. The following figure shows the proposed reaction scheme for the Cu-catalyzed aerobic C-alkylation reaction (Scheme 16).95 In this case, the alcohol activation has been accomplished with ligand-free copper catalysts. These catalysts were superior than other metals in forming new C−C bonds in the form of secondary alcohols and ketones. 2.2.1.2. Knoevenagel Reaction. The modified aldol reaction known as the Knoevenagel reaction has also been used for monoalkylating C−H acid methylene compounds in combination with BH (Scheme 17). In the Knoevenagel reaction, a nucleophilic attack of an active carbanion takes place on a carbonyl group and then a dehydration reaction occurs (hence condensation) giving an α or β conjugated enone. Grigg and co-workers described one of the first homogeneous transition metal catalyzed alkylations using the Knoevenagel reaction.96 In this case, an in situ prepared rhodium catalyst (RhCl3 and PPh3) catalyzed the transformation of a series of arylacetonitrile derivatives into monoalkylated arylacetonitriles, the latter being applied as intermediate products for the synthesis of acids, amides, and heterocycles as well as biological active substrates. Curiously, aromatic acetonitriles and primary alcohols were reacted in the presence of a rhodium complex in combination with triphenylphosphine and KOH for the synthesis of αarylacetamides under microwave-assisted conditions.97 Nonetheless, as in previous sections, Ru and Ir-based complexes have shown again much higher reactivity for this reaction as compared to the in situ prepared rhodium catalyst above-mentioned.96 Indeed, the Grigg’s group reported a practical alkylation reaction of nitriles catalyzed by an iridium catalyst through an indirect Knoevenagel reaction using in some cases microwave activation.98 In this case, a wide range of nitriles and alcohols, including indole and pyridine derivatives, could be selectively converted into the desired products in very high yields. For example, the alcohol derivative and 3pyridylacetonitrile were reacted to yield the corresponding monoalkylated nitrile with a striking shortening of reaction time (from 17 h to 10 min) when the reaction was assisted by microwave (MW) radiation. The same catalyst, as well as related iridium complexes, were applied for the alkylation of 1,3-dimethylbarbituric acid (highly important molecule in the synthesis of pharmaceuticals) and alkyl cyanoester derivatives.99−102 For example, the microwave assisted indirect monoalkylation of 1,3-dimethylbarbituric acid (40) with alcohols was carried out in the presence of a bimetallic Ir(III)/Pd(0) catalyst to give the corresponding monoalkylated products (41) and by extension the spirocyclic barbiturates (42) in one-pot (Scheme 18).99 The use of both transition metal elements was compatible. In this approach, Ir(III) catalyzed the monoalkylation reaction at the 5 position of the dimethyl barbituric acid derivative using benzyl and aliphatic alcohols. In a particular case, the oxidative

a Adapted with permission from ref 88. Copyright 2014 Royal Society of Chemistry.

Scheme 14. Examples of Cationic and Neutral Iridium(I) Complexes (36−39 and 32−35 Compounds, Respectively) with Functionalized NHC Ligandsa

a


imidazolium salts. The catalysts were successfully applied in the β-alkylation reaction of 1-phenylethanol with benzyl alcohol as a model reaction. Besides, the catalysts yielded a mixture of βalkylated alcohols and α-alkylated ketones starting from different alcohols. Some selected examples are given in Table 2.91 Finally, it is important to highlight the case of an iridiumbased complex which was successfully applied for the formation of α,ω-diarylalkanes from primary alcohols by combining a Guerbet reaction (β-alkylation of alcohols) with other transformations (Scheme 15).92 In this case, the alkylated alcohol initially formed experienced a clean route to α,ω-diarylalkanes through a successive dehydrogenation/deoxidative addition (to the Ir catalyst), followed by CO extrusion with β-hydrogen elimination as well as a final reduction step of the intermediate compound 28, as depicted in the Scheme 15.92 Palladium has also been used as a catalyst in cross-coupling reactions of primary and both secondary and primary alcohols to give β-alkylated alcohols as described by different groups.93,94 As an example, in the presence of a pincer-type NHC/PdBr complex, the reaction (under either Ar or H2 gas) showed a broad substrate scope as well as a high alcohol product selectivity.93 Other uncommon metals that have been reported to be catalytically active for this reaction are for instance Cu(OAc)2· 1418


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Table 2. β-Alkylation of Secondary Alcohols with Primary Alcohols Catalyzed by Iridium(I) Complexes 33 and 37 Having an NHC Ligand with a 2-Methoxybenzyl Substituenta,b

a

Adapted with permission from ref 91. Copyright 2015 Wiley-VCH. Reaction conditions: catalyst (0.003 mmol, 1 mol %), catalyst/secondary alcohol/Cs2CO3 ratio 1:100:100 and primary alcohols (3.6 mmol), in toluene (0.3 mL) at 110 °C for 3 h. bDetermined by GC analysis based on the secondary alcohol by using mesitylene as internal standard. cCatalyst/base ratio of 1:150. dYield of the isolated β-alkylated alcohol product 27.

Scheme 15. Plausible Reaction Pathway for the Formation of 1,3-Diphenylpropane 27 Starting from Phenethyl Alcohola

a


Scheme 16. Proposed Reaction Scheme or the Cu-Catalyzed C-Alkylation of Alcohols with Alcoholsa

Scheme 17. Hydrogen Autotransfer Combined with Knoevenagel Reaction

a Reproduced with permission from ref 95. Copyright 2012 Royal Society of Chemistry.

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Scheme 18. Microwave Assisted One-Pot Synthesis of Monoalkylated 1,3-Dimethylbarbituric Acid 41 Followed By Spirocyclization to Give Compound 42 in the Presence of a Dual Ir(III)/Pd(0) Catalytic Systema

a

Reproduced with permission from ref 99. Copyright 2006 Royal Society of Chemistry.

Table 3. Optimization of Reaction Conditionsa

entry

catalyst (mol % metal)

base (mol %)

13a (eq )

yield (%)b

TOF (h−1)c

1 2 3 4 5 6 7 8 9 10 11 12 13d

[Cp*IrCl2]2 (1) Pd(OAc)2 (1) Pd/C (1) [RuCl2(p-cymene)2]2 (1) [RuCl2(p-cymene)2]2/2dppf (1) RuCl2(p-cymene)2 RuCl2(PPh3)3 (1) RuCl2(PPh3)3 (1) RuCl2(PPh3)3 (0.5) RuCl2(PPh3)3 (1) RuCl2(PPh3)3 (1) RuCl2(PPh3)3 (1) RuCl2(PPh3)3 (1)

KOH (20) KOH (20) KOH (20) KOH (20) KOH (20) KOH (20) KOH (20) K2CO3 (20) K2CO3 (20) K2CO3 (5) − K2CO3 (5) K2CO3 (5)

2 2 2 2 2 2 2 2 2 2 2 1.2 1.2

78 68 77 26 88 84 96 98 42 99 30 99 95

25 32 22 − 37 51 53 − − − − − −

a

Reproduced with permission from ref 104. Copyright 2017 Elsevier. Reaction conditions: mixture of 1a (1 mmol), 13a (1.2 or 2 equiv), catalyst (1 mol % metal), and base were heated at 120 °C in toluene for 24 h. bDetermined by 1H NMR. cDetermined at initial conversion points after 30 min. d For 8 h.

diverse ruthenium complexes and catalytic amounts of a base (Table 3).104 The catalytic system was also active using aliphatic alcohols, whereas different substituents on the nitrogen atom of the molecule were well-tolerated. This ruthenium-based catalytic system was applied to the synthesis of acid-fused benzopyrane derivatives 45 through the alkylation of barbituric derivative 40 with salicylic alcohols (44a−44c) followed by treatment with a strong Brönsted acid in one-pot (Scheme 19).104 It is interesting to note that the synthesis of γ-butyrolactone derivatives (48) has also been recently reported to take place using the BH strategy though integrated in an intensive sequential-type approach. This strategy combined a Knoevenagel reaction with an intramolecular cyclization, by reacting malonate derivatives (47) and 1,2-diols (46) in the presence of a Ru complex as catalyst as depicted in the scheme (Scheme 20).105 Besides the traditional ruthenium and iridium complexes, other uncommon transition elements such as cobalt and osmium have been exceptionally applied in this type of reaction.106,107 For example, it is necessary to highlight the alkylation (50a−l) of amides (49) and esters with alcohols (13) through BH methods by using the Knoevenagel reaction as intermediate reaction and cobalt complexes stabilized with pincer ligands (51). One of the most interesting features of this approach is that the Co(II) complex can be prepared on a

addition of Pd(0) to one aryl iodide derivative followed by allene insertion would generate a π-allyl Pd(II) complex. This species would undergo a regio and setereoselective intramolecular nucleophilic attack of the C5 barbiturate carbanion at the least hindered sp2-carbon giving the E-alkene (Scheme 18).99 The importance of this approach relies in the fact that there is not a straightforward synthetic procedure for the synthesis of 5-monoalkylated barbituric acid derivatives. Therefore, for forming such important intermediates the direct alkylation with alcohols by means of BH strategies is an attractive alternative. Other iridium-catalyzed C-alkylations using alcohols and nitroalkanes (nitroaldole reaction), as well as 1,3-diketones, ketonitriles, and malonates103 should be highlighted. With respect to ruthenium catalysts, it is important to indicate that [RuH2(PPh3)3(CO)]/Xantphos catalyzed the Calkylation of ketonitriles with benzylic alcohols with much lower metal loading (0.5 mol %) and giving the alkylated products in high yields, whereas the catalyst RuCl2(PPh3)3104 successfully monoalkylated barbituric acid. In this particular case, 1,3-dimethylbarbituric acid 40 was monoalkylated with benzyl alcohols and heteroaromatic alcohols giving from good-to-excellent yields of the corresponding alkylated barbituric derivatives (43) in the presence of 1420


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In order to finalize this section we will refer to arylacetonitriles107 that were also recently alkylated with primary alcohols (13) in the presence of an uncommon osmium catalyst, being included in a previous specific review on BH catalysis. 2.2.1.3. Decarboxylative Knoevenagel Reaction. Another interesting route involving the use of malonate half esters for alkylation reactions has also been considered according to the pathway outlined in Scheme 22.108

Scheme 19. Examples of One-Pot Synthesis of FusedBenzopyrans 45a−45c Starting from 1,3-Dimethylbarbituric Acid (40) and Salicylic Alcohol Derivatives 44a−44ca

Scheme 22. Hydrogen Autotransfer Combined with a Decarboxylative Knoevenagel Reaction

a

Adapted with permission from ref 104. Copyright 2017 Elsevier.

Scheme 20. Schematic Transformation Involved during the Synthesis of Lactone Derivativesa

In this work the temporary removal of hydrogen from the alcohol generates an aldehyde that undergoes a decarboxylative Knoevenagel reaction with malonate half ester giving the α,βunsaturated ester. Finally, a last hydrogenation step yields the desired ester. The decarboxylative Knoevenagel reaction of aldehydes is a well-known process, which is usually catalyzed by a suitable amine.109 Indeed, in one of the pioneering works pyrrolidine was chosen as the organocatalyst on its ability to carry out the decarboxylative Knoevenagel process,109 in the presence of a Ru(PPh3)3Cl2 catalyst. Since the only byproducts formed in this case were water and carbon dioxide, this process

a

Adapted with permission from ref 105. Copyright 2015 Royal Society of Chemistry.

multigram scale and can be activated under basic conditions (Scheme 21).106

Scheme 21. Product Scope for Amide Alkylation with Cobalt Complex 51a

a

Reproduced from ref 106. Copyright 2016 American Chemical Society. 1421


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catalyst. The cyano indole derivative was alkylated to give the corresponding alkylated cyano indole derivative. Consistent with previous observations N-methylindole failed to afford methylation. This observation points to an anion intermediate as the key compound involved in the reaction mechanism. The detection of bisindolylmethane (54) as secondary product formed through the Michael addition of indole 52 to the intermediate product 53 gives strong support to this reaction route. Other examples refer to interesting applications with different Ir catalysts. These studies describe the synthesis of a series of monoamine alkaloids derived from tryptamine through the C3-alkylation of indole, as well as the C3-alkylation of oxindole (2-indolone).114 In this last case, the reaction could be carried out under neat conditions under thermal or even microwave conditions.114−116 There is another particular case with iridium-based complexes, which slightly deviates from the general established reaction scheme and describes the C-alkylation of Nheteroaromatics.117,118 This study describes the C- and Nalkylation of pyrimidinyl amine derivative 55 using simple alcohols (13a) in the presence of an iridium complex (57) (Scheme 25).117

provides a useful alternative to the Wittig reaction for the conversion of aldehydes into α,β-unsaturated esters.110 2.2.1.4. Conjugate Addition. Only one example of conjugate addition as intermediate reaction in BH strategies has been found in literature, being a reference treated in previous reviews. Given that no more examples have been published to date, we will then describe this example to illustrate the importance of such intermediate reaction in the context of BH processes. This study consists of an indirect nucleophilic addition of methylmalonitrile and benzylmalonitrile to different cycloalkenols to give the corresponding addition products.111 The plausible reaction pathway when the allylic alcohol cyclohexen1-ol was put in contact with methylmalonitrile is depicted in the following scheme (Scheme 23):111 Scheme 23. Catalytic Activation of Cyclohexen-1-ol Allows the Conjugate Addition and Subsequent Reductiona

Scheme 25. Observed C- and N-Alkylation of a Pyrimidinyl Amine Derivative 55 with Benzyl Alcohol 13aa

a


a


The utility of this strategy relies on the fact that the catalytic electronic activation of the substrate makes possible the addition of the nucleophile to an allylic alcohol contrary to what could be expected. 2.2.1.5. C3-Alkylation. Some years ago, Grigg and coworkers reported the synthesis of alkylated indoles using alcohols as hydrogen donors,112 and more recently pyrrole and indole (52) molecules were alkylated with methanol using the same iridium complex as catalyst affording the corresponding methylated derivatives in high yields (53) (Scheme 24).113 The scope or generality of the alkylation of indoles was studied under optimized conditions, and the results showed that indole derivatives with electron-donating or electronwithdrawing groups on the phenyl ring took place smoothly. Moreover, the halide substituents (fluoro-, chloro-, and bromoindole derivatives) were well-tolerated under the experimental conditions, giving the corresponding alkylated indoles in good yields. Curiously, the nitro group at the indolic ring was easily reduced in the presence of methanol and the same iridium

In this case, the dehydrogenation of the alcohol and subsequent reaction of the resulting aldehyde with a heteroaromatic substrate (beforehand deprotonated by stoichiometric amounts of a strong base) led to the aldol product. The latter rapidly eliminated water at elevated temperatures giving an olefinic substrate onto which the borrowed hydrogen equivalents were incorporated to yield the final alkylated product (56). As expected, this catalytic reaction has also been examined with ruthenium complexes, in particular, new (arene)ruthenium(II) complexes featuring phosphinosulfonate ligands. These complexes catalyzed the alkylation of cyclic amines with alcohols using camphor sulfonic acid as an additive.119 2.2.1.6. Wittig Reaction. Ketones and aldehydes can also be involved in Wittig reactions to afford new carbon−carbon double bonds. Hence, by means of the BH strategy, hydroxyl groups can be transformed into aldehydes, which can undergo

Scheme 24. Iridium-Catalyzed Methylation of Indole (52) with Methanola

a

Adapted with permission from ref 113. Copyright 2015 Royal Society of Chemistry. 1422


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Wittig type reactions to give new alkenes (Scheme 26). Then, the metal hydride will hydrogenate the double bond giving the corresponding saturated compound.

Scheme 28. Synthesis of Ruthenium Complex 62 Reported by Burling et al.a

Scheme 26. Indirect Wittig Reaction Using Alcohols

a Reproduced from ref 122. Copyright 2007 American Chemical Society.

2.2.1.7. Diene-Ketone Reductive Coupling. Details on the evolution of carbonyl addition chemistry have been given in an recent excellent review by Krische et al.124 The same authors have described examples on the catalyzed diene-ketone reductive coupling via hydrogen autotransfer in a few and significant examples that will be described below.125,126 These studies have been carried out with ruthenium catalysts which enabled the reductive coupling of activated ketones and dienes (64) from secondary alcohols (65). Mechanistic studies revealed that there is a diene-carbonyl (63, 64) oxidative coupling to give an oxaruthenacycle. Then a hydrogen transfer from the alcohol would afford the metalacycle hydrogenolysis, from which the C−C coupling product (66) would be released, regenerating the ketone and closing the catalytic cycle (Scheme 29).126 Besides α-hydroxyesters125 and heteroaryl substituted secondary alcohols,126 the process also applies to 3-hydroxy2-indoles.127 2.2.2. Formation of C−N Bonds. 2.2.2.1. Aza-Wittig Reaction. Examples of aza-Wittig reaction going in tandem with dehydrogenation/hydrogenation reactions have been described also in recent literature reviews. Given that there are no further examples on this intermediate reaction, we will describe these same examples to illustrate this section. In this case, the nitrogen analogue of a Wittig olefination reaction (aza-Wittig reaction) involved in a BH strategy has been reported to give remarkable yields of the corresponding secondary amines (up to 91%) in the presence of an in situ generated Ir complex under moderate reaction conditions.128 Besides a similar process can take place with palladium(II) acetate as catalyst and a strong base as depicted in the following scheme (Scheme 30).129 In this case, and in an analogous manner to phosphorus ylides in the Wittig reaction, phosphazenes or iminophosphoranes (67) reacted with carbonyl compounds formed in situ through a dehydrogenation reaction from an alcohol (13a), being the product converted immediately after, to the corresponding secondary amine (68a). Modest yields (25%) were obtained by adding potassium carbonate, although this yield could be increased up to 94% when a stronger base such as cesium hydroxide was incorporated in the reaction media. Borrowing hydrogen catalysis was in this case a good strategy for forming C−N bonds, albeit the substrate scope was restricted to primary alcohols. Another important disadvantage was the need for large amounts of base as an additive. Similarly, benzyl alcohol (13a) and phosphazene (67) reacted in the presence of the base tBuOK to give the expected amine with good yields in the presence of Cu(OAc)2 as catalyst.130 2.2.2.2. Condensation. 2.2.2.2.a. N-Alkylation of Ammonia (Amination of Alcohols with Ammonia). Besides the Aza-

In this sense, Williams et al. reported a set of indirect Wittig type reactions, such as the iridium-catalyzed indirect HornerWadsworth-Emmons reaction of benzyl alcohol (13a) with phosphonates (60)120 or Wittig reactions with cyano ylides (58)121 to get the corresponding dihydrocinnamate (59) and propionitrile derivatives (61) (Scheme 27). Both references Scheme 27. Examples of Indirect Wittig As Well As HornerWadsworth-Emmons Reaction Using Benzyl Alcohol 13aa

a

Adapted with permission from ref 120. Copyright 2002 Wiley-VCH. Adapted with permission from ref 121. Copyright 2006 Wiley-VCH.

were cited in specific reviews, but given that no further examples have been reported since then, these two examples will be described below in order not to lose the perspective of the variety of intermediate reactions that can take part in BH processes. For example, in the present scheme the general indirect Wittig as well as Horner-Wadsworth Emmons reactions using benzyl alcohol in the presence of the same iridium complex and base Cs2CO3 are depicted (Scheme 27).120,121 The catalysts showed a high tolerance and compatibility with a wide variety of functional groups. The same happened to the series of ruthenium catalysts that have been applied in this reaction. For example, the ruthenium carbene complex (62), synthesized upon heating Ru(PPh3)3(CO)H2 with 4 equiv of IiPr2Me2 (Scheme 28),122 was also described as a catalyst for the indirect Wittig reaction of alcohols with phosphorane ester ylides and cyano ylides. This generation of ruthenium complexes was very active at lower temperature, although a hydrosilylation additive (vinyltrimethylsilane) was necessary to activate the catalyst. Under these experimental conditions, high yields of the final products could be achieved.123 1423


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Scheme 29. Postulated Hypothetical Mechanism through a Stable Oxaruthenacycle (Framed in a Box) Involving DieneCarbonyl Oxidative Couplinga

a


Scheme 30. Example of an Indirect Aza-Wittig Reaction between the Iminophophorane Derivative 67 and Benzyl Alcohol (13a)a

a

Scheme 31. Catalytic BH Process for the Amination of Alcohols with Ammonia

Adapted with permission from ref 129. Copyright 2011 Thieme.

Wittig reaction, there are other synthetic well-known procedures to synthesize amines. Among them the classical reductive amination which is of special industrial importance as it constitutes one of the most common methods to produce lower alkyl amines.14,41 The main reason for the large scale use of this reaction is, on one hand, the availability of aldehydes from the respective alcohol precursor. Indeed, the latter are obtained through important industrial processes such as hydration of olefins, hydroformylation/reduction of alkenes, fermentation of sugars or direct production from synthesis gas.131 On the other hand, ammonia is cheap and can be used with very high atom efficiency in the synthesis of structurally different amines, so that several million tons of amines can be produced annually.41 In close connection to this, it is possible to address the reductive amination through the N-alkylation of alcohols with ammonia by following the BH methodology. In accordance with this methodology, there is an initial common alcohol oxidation step to the corresponding aldehyde or ketone. The latter will react with ammonia through a condensation reaction giving an imine and water as the only secondary byproduct; something which is obviously far less problematic than the generation of inorganic salts formed in several amination reactions (e.g., using alkyl or aryl halides).The imine will be hydrogenated in the last step by the metal hydrides formed in the initial dehydrogenation reaction (Scheme 31). Nonetheless, one important advantage of the BH methodology should be emphasized against the classic reductive amination. This advantage refers to side reactions that can easily occur in classic reductive aminations due to the high concentration of the electrophilic aldehyde (e.g., aldol condensation), and that can not take place in the BH strategy, since the aldehyde formed by dehydrogenation in BH strategies

is only present in small amounts since it is formed and consumed continuously in situ. Another important issue in the context of aminations of alcohols is the identification of the real mechanism, through acid-, base-catalyzed reaction or by the BH methodology (which is the object of this chapter). In this sense, the detection of intermediates such as imines or ketones is a clear indication of oxidation and strongly suggests a BH mechanism. One of the first groups that studied the preparation of primary amines using inexpensive ammonia was the Milstein’s group by using ruthenium coordinated to a hemilabile PNP acridine ligand.132 Later on, the mechanism of the amination reaction of alcohols with ammonia catalyzed by ruthenium coordinated to structurally more common ligands [(e.g., diphosphine (oxidi-2,1-phenylene)-bis(diphenylphosphine) (DPEphos)] was proposed by Baumann et al.133,134 Almost in parallel, attempts to get primary amines from secondary alcohols and ammonia in the presence of [Ru3(CO)12] and commercially available CataCXium PCy were independently reported by two groups.135,136 Similarly a broad screening of ruthenium catalysts, reaction conditions, and ligands were tested in different reactions with ammonia leading to the amination of alcohols for the synthesis of diamines, aminoesters,137 α-amino acid amides138 (important structures in different bioactive compounds) and the amination of bioalcohols.139 For example, on the basis of the previously mentioned Ru3(CO)12/CataCXiumPCy system, a variety of ligands (69−76) were screened in order to find a more robust catalytic system. The authors found that compound 72 exhibited a high activity for transforming a series of primary 1424


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Figure 4. Collection of ligands tested in the amination reaction of cyclohexanol as model alcohol. Adapted with permission from ref 139. Copyright 2013 Wiley-VCH.

and secondary bio monoalcohols and bioderived diols into primary amines (Figure 4).139 Interestingly, the Ru/P ratio employed had a strong effect on the reaction rate, so that a 1:1 ratio appeared to be the optimal, whereas a higher ratio (Ru/P = 1:0.66) showed a similar activity initially but led to deactivation of the catalyst as the reaction was evolving with time. The following table includes the most interesting results obtained in the secondary bioalcohol amination with the system Ru(CO)12/72 at different temperatures (Table 4).139 Examples of N-alkylations with ammonium salts and aqueous ammonia as an alternative to ammonia gas are scarce. In fact, only one example of each type has been reported in the literature that have been already included in previous specific reviews. Nonetheless, given their importance they will be quoted below describing their advantages and disadvantages for the information on readers. For example, an interesting study reported the use of ammonium acetate as precursor for the in situ generation of ammonia in the amination of alcohols (using classical iridium catalyst ([Cp*IrCl2]2).140 This strategy led to the obtention of trialkylamines. However, though a priori the unnecessity of a pressure equipment turns a reaction into a more practical process; a problem in this case arises because the use of ammonium salts generate stoichiometric amounts of waste salts. An alternative would be the use of aqueous ammonia as shown in the hexanol and cyclohexanol amination to give tertiary and secondary amines reported by Fujita et al.141 Notably the catalyst could be recycled and reused up to three times by adding a solvent followed by a phase separation. It is important to emphasize that the use of ruthenium and iridium complexes has been extensively reported for the synthesis of amines, aminoesters, aminoalcohols, and diamines in the patent literature in parallel to academic reports which have used similar or closely related metal-based complexes. This highlights the importance of these two elements to academic and industrial practice.137,142−148 Nonetheless, along with ruthenium and iridium, other less usual elements such as platinum have been reported to produce allylamines (78, 79) from the corresponding allylic alcohols (77) and ammonia.149 In this new protocol, a variety of primary allylamines (78a−h) were obtained in a straightforward fashion from the respective allylic alcohol in aqueous ammonia (28%). Unexpectedly, in this case the reaction with ammonia excess afforded a lower yield because of the partial deactivation of platinum. However,

Table 4. Secondary Bioalcohol Amination with [Ru3(CO)12]/72 at 150 and 170 °Ca

a

Adapted with permission from ref 139. Copyright 2013 Wiley-VCH. Reaction conditions: [Ru3(CO)12] (0.066 mmol), 72 (2 mmol), substrate (10 mmol), tert-amyl alcohol (13.3 mL), NH3 (6 mL, 234 mmol), 150 and 170 °C. bConversion determined form GC analysis on the basis of alcohol consumption and amine production. cTotal of all primary amines. dMain byproducts are primary imines, amides, and ketones.

under optimized conditions, the allylic alcohol amination catalyzed by this metal was rather general. A collection of the most interesting results are included in the following table (Table 5).149 2.2.2.2.b. N-Alkylation of Primary and Secondary Amines (Amination of Alcohols with Primary and Secondary Amines). The amination of alcohols with primary amines by the BH methodology has the advantage of promoting the production of secondary amines because a primary amine can react more easily with the aldehyde. This fact contrasts sharply 1425


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condensation of the resulting carbonyl group to give imines, and the subsequent reduction of the latter to give amines, which are basically the demanded requirements for these catalytic systems.10,12,14−17,19,57 Primary alcohols have mainly been used as hydrogen donors for the amination reactions, provided they were more reactive compared to secondary alcohols. Looking back to the origins of this reaction we found that one of the first homogeneous catalysts for N-alkylation of amines with alcohols was introduced by Grigg et al.151 and Watanabe et al.152 in 1981. Grigg et al. reported the Nalkylation reaction of primary and secondary amines with primary alcohols, to give secondary as well as tertiary amines, being a rhodium catalyst [RhH(PPh3)4] the most active one.151 In parallel, Watanabe and co-workers reported the rutheniumcatalyzed N-alkylation and N-heterocyclization of aniline with alcohols and aldehydes. In both reactions, only primary alcohols were applied as hydrogen donors.152 From this background, N-alkylations for forming secondary amines (by reacting primary amines with alcohols)5,153−170 and amino alcohols171,172 have been extensively reported in the literature. At this point, it is necessary to emphasize that iridium and ruthenium complexes have been again the dominant catalysts in these types of transformations. As an example, different types of anilines have been monoalkylated with benzyl as well as aliphatic alcohols in the presence of iridium coordinated to an anionic P,N ligand (80 and 81 iridium complexes). The authors observed a nearly quantitative conversion under mild conditions (70 °C) and a very low iridium loading (0.05%) (Table 6).157 Some relatively recent applications that corroborate the interest that this reaction has awakened in large scale synthesis is the one kilogram scale application of this strategy for the synthesis of one inhibitor for the treatment of schizophrenia named PF-03463275. In particular, a GlyT1 inhibitor, which is prepared in the presence of (Cp*IrCl2)2 under optimized conditions with catalyst loadings lower than 0.05 mol %, while requiring moderate reaction times.173 Other interesting applications of Ir-based catalyst led to the N-alkylation of carbohydrate alcohols leading to N-substituted aminosugars with potential applications in the biochemical and pharmaceutical fields.174 Similarly, Fujita et al. reported that [Cp*IrCl2]2 efficiently catalyzed the coupling between different amines and monoalcohols, or even vicinal diols for the synthesis of Nheterocycles,175,176 whereas a related Ir compound [Cp*IrI2]2 was also successfully applied in this reaction in a more benign aqueous media and without requiring the use of a base.159 Besides, the synthesis of N-heterocycles through an intramolecular reaction of amines has also been described to take place in the presence of closely related Ir-based catalysts.177 A related Cp* Ir half sandwich complex with amino acidato ligands has also been reported to catalyze the alkylation of amines with alcohols under milder conditions.178 Continuing with iridium, a cyclometalated iridium complex (84) has shown a similar substrate scope for the synthesis of secondary amines (83) (albeit its extraordinary activity was limited by a strong solvent effect) (Scheme 33).179 With regard to ruthenium, diverse ruthenium(II) carbonyl complexes bearing phosphine-functionalized hydrazine/thiosemicarbazone ligands and triphenylarsine ligands were prepared, being characterized by different techniques. In all these complexes, ruthenium(II) was coordinated with the ligand via

Table 5. Amination of Allylic Alcohols with Aqueous Ammonia Catalyzed by Pt(cod)Cl2a

a

Adapted with permission from ref 149. Copyright 2012 Wiley-VCH. Reaction conditions: 77 (0.5 mmol), [Pt(cod)Cl2] (1 mol %), DPEphos (2 mol %), 28% aq. NH3, 1,4-dioxane and MeOH (3:2:1, total volume 6.0 mL), 100 °C in sealed tube. bDetermined by 1H NMR spectrum of the crude reaction mixture. The number in parentheses is the yield of the isolated product after Boc protection. c 79 was not detected by either 1H NMR or CI-MS analysis of the crude reaction mixture. d3.0 mol % of catalyst was used.

with classical alkylation methods which tend to give overalkylation products because the secondary amine is more reactive than the primary one toward the alkyl bromide. As in the previous case with ammonia, the BH methodology only generates water as byproduct and allows alcohols to replace more conventional but often toxic alkyl halides as alkylating agent.150 The process occurs analogously through three in situ consecutive reactions: dehydrogenation, condensation, and hydrogenation (Scheme 32). Scheme 32. Catalytic Condensation and Borrowing Hydrogen Methodology Going in Tandem for the NAlkylation of Amines with Alcohols

The great potential of this reaction has stimulated a growing number of applications of BH chemistry on N-monoalkylations, so that the development of active homogeneous catalysts has greatly increased. The strategy for designing new catalysts has gone through the synthesis of new molecularly defined organometallic catalysts or the modification of other already existing ones. The result has been a wide collection of metal active complexes for the oxidative dehydrogenation of alcohols, 1426


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Table 6. Catalytic N-Alkylation of Anilines Derivatives with Primary Alcohols in the Presence of Iridium Catalysts 80 and 81a

a Adapted with permission from ref 157. Copyright 2010 Wiley-VCH. Reaction conditions: amine (1.0 mmol), benzyl alcohol (1.1 mmol), KOtBu (1.1 mmol), diglyme (0.2 mL), 70 °C, 24 h. bYield determined by GC analysis with n-dodecane as the internal standard.

PNO/PNS donor atom being actives at very low catalyst loading. Figure 5 shows the structure of some of the ruthenium−phosphine-based catalysts (84−88) of this study.180 Another interesting sort of ruthenium complexes were prepared from readily available 1,3-dialkylbenzimidazolium salts, being characterized by X-ray diffraction. Interestingly, the RuNHC complexes (92−94) efficiently promoted the catalytic N-alkylation (90) as well as the N,C-dialkylation (91, see section 2.2.1.5) reaction of different cycloaliphatic amines like morpholine and pyrrolidine (89).169 Table 7 shows some of the results obtained on the N-alkylation and C3 alkylation of pyrrolidine with different benzylic alcohols. Different ruthenium catalysts have also been prepared in situ by adding benzimidazolium sulfonate salts into the reaction mixture. The system [RuCl2(p-cymene)]2/benzimidazolium sulfonate salt was active at 120 °C under neat conditions for the selective N-alkylation of primary aromatic amines (aniline) with benzyl alcohol into secondary amines. The following scheme (Scheme 34) shows the preparation of the

benzimidazolium sulfonate salts (96) from benzimidazole (95) according to the synthetic method described in ref 181. More recently a set of benzimidazolium sulfonate salts (98) have been incorporated as additives in [RuCl2(p-cymene)]2 catalyzed reactions to give a very active complex for the obtention of secondary amines starting from aromatic primary amines. For example, the synthesis of amine 68a starting from benzyl alcohol (13a) and aniline (9a) takes place with the incomplete hydrogenation of the corresponding imine 97 (Scheme 35).181 In another approach, a tunable amidation/amination reaction has been described to occur in the presence of a ruthenium NHC/phosphine complex. In accordance with these results, the amide derives from an acceptorless dehydrogenation process that involves the participation of a hemiaminal compound, meanwhile the “borrowing hydrogen” process takes place just for forming the amine (Scheme 36).182 The authors point out that the selectivity is based on the tuning of the N-proton transfer. This N-proton transfer can be easily tuned by changing the base and the solvent. The protonto-hydrido transfer gives rise to amides; though the proton-to1427


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Scheme 33. Cyclometalated Iridium Complex Catalyzed N-Alkylation of Primary Amines (82) with Secondary Alcohols (13) Reported by Xiao and Coworkersa

a


Figure 5. Collection of ruthenium-phosphine-based catalysts 84−88 for the amine synthesis from alcohols and schematic synthetic strategy for their preparation. Adapted with permission from ref 180. Copyright 2015 Elsevier.

secondary amines such as morpholine, piperidine, 1-phenylpiperazine, and 1-Boc piperazine (107) forming the corresponding aminated products (108) in up to 92% isolated yield. The synthesis of an antitussive molecule 109 in up to 86% yield from solketal showed the utility of this methodology (Scheme 38).189 Similarly, a variety of structurally complex Ru(II) catalysts (e.g., 113) have also been described to have activity in the Nalkylation of sulfonamides as well as heterocyclic amines (e.g., 110) in the presence of KOH (Scheme 39).190 Finally, we will refer to the possibility of synthesizing pyrrole far from those traditional routes suffering from harsh reaction conditions, nonavailability of raw materials, and poor functional tolerance, through a hydrogen autotransfer process. In this case (Scheme 40), iron-based complex catalyzed the amination of diols using primary amines.191 In light of these findings, it is fairly clear that mainly primary alcohols have been used as hydrogen donors for amination reactions over any other type of alcohol, provided that with few exceptions they are much more reactive compared to secondary alcohols.153,159,160,192 Nonetheless from now on, we will focus on studies about Nalkylation of amines through activation of secondary alcohols. In this context, the use of ruthenium complexes has attracted attention as catalysts for this strategy. Indeed, a few number of examples on the activation of secondary alcohols by ruthenium

alkoxide transfer will give an imine. The latter can be hydrogenated by the ruthenium hydride intermediate complex affording amines (Scheme 36).182 A novel ruthenium catalysts (102) was prepared and characterized by using the benzimidazolin-2-ylidene N-heterocyclic carbene as ligand.183 This catalyst was successfully applied for the synthesis of N-alkylated amines such as cyclic amines (101) from amines (100) and diols (99) (Scheme 37).183 Previously, the homogeneously catalyzed N-alkylation of a poor nucleophile heterocycle such as indole (hence the importance of this reference) with alcohols,184,185 the amination of 1,2-diols with anilines and secondary amines,186 as well as the preparation of unsymmetrically tertiary amines from tertiary amines and primary alcohols in the presence of ruthenium complexes were reported.187 Another ruthenium(II) complex [Ru(COD)Cl2] efficiently catalyzed the synthesis of trisubstituted 1,3,5-triazines (105) by reacting alcohols (103) and biguanides (104). The method had a broad scope, and a variety of functional groups showed high group tolerance. The Table 8 shows some interesting results for obtaining triazines.188 Another interesting application has to do with the transformation or upgrading of glycerol with primary and secondary amines. Indeed, isopropylideneglycerol (106) can be aminated in its primary position with [Ru(p-cymene)Cl2] and a variety of 1428


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Table 7. N-Alkylation and N,C3-Dialkylation of Pyrrolidine with Benzyl Alcohol Derivativesa

alcohols by BH methodology using available and cheaper metals such as iron, copper, cobalt, palladium, silver, gold, and osmium.196−202 Indeed, it is evident that the use of complexes based on nonprecious metals provides us with new opportunities in the N-monoalkylation of amines with alcohols. In this sense, Beller et al. have recently reported for the first time the use of a manganese pincer complex as catalyst for the N-alkylation of aromatic amines and primary alcohols (Scheme 43).203 The complexes (124−127) were highly stable being easily handled under air. In this case, it was possible to get high yields of the corresponding secondary amines, being the presence of different functional groups on the starting reactants welltolerated under very mild conditions.204,205 Finally, a last example reported the excellent performance of an iron cyclopentadienone complex when a variety of alcohols and amines reacted to yield secondary amines and Nheterocycles.206 2.2.2.2.c. N-Alkylation of Amides and Sulfonamides. The same previous synthetic BH methodology can be applied to the N-alkylation of amides by alcohols. The reaction pathway depicted in Scheme 44 shows a close analogy to that described in previous sections. In a similar way to what was observed when using amines as substrates, different metal-based complexes were successfully applied as catalysts for the N-alkylation of amides, including iridium, ruthenium, palladium, as well as rhodium complexes.207,208 Nonetheless, we owe the early efforts on this issue to Watanabe, who described one of the first ruthenium-catalyzed formation of substituted amides through the N-alkylation of amides with alcohols.209 Since then, only two studies on amide alkylation by means of BH methodology have appeared in the literature,207,208 being already included in specific reviews. Given that further studies have not been published so far, these two previous references will be described below. However, not only amines and amides are suitable candidates but sulfonamides are also good substrates to carry out alkylation reactions at the N position following the BH strategy.207,208,210−213 Indeed, the interest of N-alkylated sulfonamides relies on their importance in agrochemical and pharmaceutical chemistry.214−216 They are also relevant as protecting groups in synthetic chemistry since the sulfonyl group can be easily removed when bound to nitrogen, allowing the N-alkylated sulfonamides to be rapidly converted into the corresponding primary amines.217 Typically, the classical processes for synthesizing N-alkylated sulfonamides are performed by reacting amines and sulfonyl halides or sulfonic acids activated by triphenylphosphine distriflate, as well as through the reductive amination of aldehydes.218 However, these previous processes have the inconveniences of giving secondary products and/or the need for sensitive substrates. Hence, the use of alcohols as alkylating reagents for

a Reproduced from ref 169. Copyright 2015 American Chemical Society. Reagents and conditions: pyrrolidine (1.0 mmol); alcohol (2.5 mmol); CSA (40 mol %); Ru-NHC (1 mol %); toluene (1 mL); 120 °C, 16 h. The yields of 90 and 91 were determined by GC using dodecane as an internal standard.

complexes have been found in the literature in the past decade giving from moderate to good yields of the respective secondary and tertiary amines.193,194 One recent contribution on the activation of secondary alcohols by Ru complexes (119) was described by Marichev et al.195 In this case, the amination (115) of primary and secondary alcohols (117a) as well as diols yielded the corresponding secondary, tertiary, and N-heterocyclic amines (116, 118) under relatively mild reaction conditions (Scheme 41).195 Several variants of inter- and intramolecular cyclizations were performed through BH catalysis giving rise to piperazines (122) and diazocines (Scheme 42).195 In this regard, this scheme shows some of the most interesting structures obtained by reacting diamines (120) and diols (121) in the presence of a Ru(II) complex (123). Although the majority of publications were focused on classic ruthenium and iridium complexes, there have been numerous attempts, at the academic level, to carry out the amination of Scheme 34. Synthesis of Benzimidazolium Sulfonate Saltsa

a

Adapted with permission from ref 181. Copyright 2016 Elsevier. 1429


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Scheme 35. Benzylation of Aniline (9a) with Benzyl Alcohol (13a) Catalyzed by a Ru Complex [RuCl2(p-cymene)]2 and the Benzenosulfonate Salt 98 as Additivea

a


Scheme 36. Proposed Reaction Pathways for the Formation of Secondary Amides and Alkylated Aminesa

a


Scheme 37. N-Alkylation of Aniline Derivatives (77) with Different Diols (76) Catalyzed by a Ru-NHC-Phosphine Complex (79)a

a


N-alkylation through BH catalysis is an attractive strategy because it does not generate harmful or toxic byproducts. Besides, alcohols, are generally stable and are readily available compounds. Moreover most of these metal-catalyzed reactions for N-alkylating sulfonamides with alcohols can be successfully carried out with good activity and selectivity. Indeed, under the optimized conditions, the scope of each particular protocol (with iron, ruthenium, palladium, iridium, rhodium, and copper complexes, etc.) has been well-

demonstrated by a long list of different alkylation reactions performed with high yields of products (>90%).129,130,219,220 One of the few examples of iridium-catalyzed processes to alkylate sulfonamides has been described with the classical [Cp*IrCl2]2 complex, which is very active for reacting primary and even secondary alcohols as alkylating agents221 and Fe(II) complexes.209 Interestingly, in this case, the existence of a possible mechanism involving a Fe(II)/Fe(0) catalytic cycle was suggested on the bases of XPS analysis. 1430


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equivalent in the form of a N-nucleophile followed by deprotection is an interesting approach. Taking into account that the sulfonamide group can be easily removed as the protecting group,217 different in situ deprotection protocols have been studied with the resulting sulfonamides and different catalysts. We will include an interesting and representative example that has been mentioned in a previous specific review. Given that this is the only example that has appeared on this particular reaction, we will describe it briefly below. In this case, benzyl alcohol (13a) was readily transformed into benzylamine (82a) through an intensive process which combined a sort of reactions based on BH methods in the presence of a ruthenium-based catalytic system [Ru(pcymene)Cl2]2/DPEphos [DPEphos: oxidi-2,1-phenylene-bis(diphenylphosphine)].15,222 The initially formed N-alkylated sulfonamides obtained by borrowing hydrogen catalysis were submitted to an in situ deprotection treatment with CsF and DMF at 110 °C, or in certain cases with Mg/MeOH (Scheme 46).222 Nonetheless, even though these preparation methods gave very good yields of the desired amines, we would point out that the low atom efficiency is a common drawback to all these amination/deprotection processes. 2.2.2.4. Condensation/N-Heterocyclization. N-Heterocycles, which have attracted considerable attention due to their importance and prevalence in pharmaceuticals, materials chemistry, synthetic organic chemistry, and dyes have also been prepared through BH methods. One interesting contribution from Fujita et al. described a cyclization reaction involving 2-aminophenethyl alcohols to indoles,223 using [Cp*IrCl2]2 as catalyst, whereas later on, Eary et al. reported the cyclization of anilino alcohols to get 1,2,3,4tetrahydroquinoxalines and 2,3,4,5-tetra-1-H-benzo[b][1,4]diazepines.224 In this case, a higher catalyst loading (20 mol % [Cp*IrCl2]2) and longer reaction times than in Fujita’s work (2−5 days) were required. More recently and in close connection to this, 2,3,4,5tetrahydro-1H-1,4-benzodiazepine (134) was conveniently prepared through a one-pot ruthenium catalyzed reaction, encompassing two consecutive borrowing hydrogen cycles starting from 2-aminobenzyl alcohol (13b) and 1,2-aminoalcohol (133) (Scheme 47).225 Mechanistically, the starting benzylic amino alcohol derivative 13b could undergo a dehydrogenation reaction resulting in the formation of the corresponding benzaldehyde derivative 135, which would react with a second amino alcohol (136) giving a secondary amine (137) (Scheme 48).225 In a second borrowing, hydrogen process compound 137 may be dehydrogenated to give the intermediate compound 138, the latter would undergo cyclization to yield compound

Table 8. Scope for the Synthesis of 1,3,5-Triazine Derivatives 105a

entry

Ar

alcohol

product

yield (%)

1 2 3b 4b 5b 6b 7 8 9 10 11c 12b

C6H5 4-MeC6H4 4-MeOC6H4 3-MeOC6H4 2-MeOC6H4 2,3-(MeO)2C6H3 3,4-(MeO)2C6H3 4-FC6H4 4-ClC6H4 4-BrC6H4 2-furanyl 2-thiophenyl

13a 13d 13e 103a 103b 103c 103d 103e 13f 103f 103g 103h

105a 105b 105c 105d 105e 105f 105g 105h 105i 105j 105k 105l

74 65 71 55 70 74 83 54 63 51 65 63

a

Adapted with permission from ref 188. Copyright 2016 Royal Society of Chemistry. All reactions were performed with 1.0 mmol of 103 and 1.0 mmol of 104 using Ru(COD)Cl2 (2 mol %), and dioxane (5 mL) at 100 °C for 14 h in a sealed reaction tube, isolated yields are shown. b 20 h. c30 h.

A more recent contribution has reported the synthesis and characterization of a variety of ruthenium complexes bearing 2(2-(diphenylphosphino)benzylidene)-N-ethylthiosemicarbazone (PNS-Et) ligands (128−130), which were revealed as very efficient catalysts in the N-alkylation of different sulfonamides with alcohols (Scheme 45).190 In order to explore the scope of the present method, the Nalkylation reaction (132) of a variety of primary sulphonamides (131) with benzylic and cycloaliphatic alcohols was tested by using the previously reported Ru(II) catalysts (Table 9).190 The authors observed that substituents on the aromatic ring of the primary sulphonamide or the benzyl alcohol had hardly influenced the alkylation reaction since the corresponding sulphonamides were obtained in very high yields (82−99%), no matter the electron-rich or electron-poor nature of the substituent (Table 9). In addition, the cycloaliphatic alcohol cyclohexanol gave the corresponding cyclohexyl sulphonamide derivative in moderate yield (entry 6, Table 9), whereas the monoalkylated methanesulphonamide was obtained with very low yields when using benzyl alcohol as a hydrogen donor (entry 7, Table 9). 2.2.2.3. Condensation/Deprotection. As previously stated, the development of synthetic methods for synthesizing primary amines is of current interest, and different experimental procedures inspired by the BH strategy have evolved in recent years. Among them, the incorporation of an ammonia Scheme 38. Synthesis of the Antitussive Dropopizine 109a

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Scheme 39. [(PNS-Et)RuCl(CO)(PPh3)] (113) Catalyzed Synthesis of the N-Alkylated Product 112 When Reacting 2Aminobenzothiazole (110) with 4-Methoxybenzyl Alcohol (111)a

a


Scheme 40. Plausible Catalytic Cycle for the Synthesis of Pyrrolea

Scheme 42. Synthesis of Diazocines and Piperazines in the Presence of a Ru(II) Complexa



be focused on designing new and more active catalysts able to activate the less reactive secondary alcohols. These complexes will also extend the scope of the BH strategy to form new carbon-heteroatom bonds not described so far, as for instance the formation of C−O, C−S, C−Si, and C−P bonds among others.

139, and ulterior hydrogenation would give the benzodiazepine derivative 140 (Scheme 48). Interestingly the use of diols, butanediol and pentanediol, as alkylating agents gave the complete conversion to substituted pyrrolidines and piperidines at low temperature and low ruthenium catalyst loading.226 To summarize this section devoted to the activation of alcohols, we conclude that alcohols (especially the primary ones) are one of the most applied hydrogen donors in borrowing hydrogen strategies, with Ru and Ir complexes as homogeneous catalysts of preference involved in a wide variety of autotransfer processes. By virtue of this BH strategy, alcohols will transform into benign and versatile alkylating agents for different scaffolds. Therefore, showing that the method is not limited to the preparation of amines (C−N bonds), but it can also be extended to form C−C bonds. In light of these precedents, we may expect that the future research efforts will

2.3. Activation of Amines

Amines might be activated, a priori, as alcohols and alkanes by dehydrogenation to provide more reactive compounds such as imines and iminium cations or enamines. Effectively, imines are produced as intermediate compounds through the Nmonoalkylation of amines with alcohols (see section 2.2.2) and can alternatively be prepared analogously to alcohols by direct oxidation of amines by hydrogen abstraction. Although this last transformation (N-alkylation of amines with amines) seems uncommon at first sight, there are many industries which are interested or involved in related transformations (see for instance transalkylation reactions) as can be deduced by the number of patents on this topic.227−232

Scheme 41. Synthesis of Five- and Six-Membered Cycloaliphatic Amines Catalyzed by a Ruthenium Complex 119a

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Scheme 43. Conversion and Yield of the N-Alkylation of Aniline with Benzyl Alcohol Catalysed by Different Mn Complexesa

a

Adapted from ref 203. Published by the Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License.

Scheme 44. Schematic Representation of the N-Alkylation of Amides

Table 9. Results of the N-Alkylation of Sulfonamides with Ruthenium Catalysts 128−130.a

Scheme 45. Structure of Ruthenium(II) (128−130) Complexes Used As Catalysts in the N-Alkylation of Sulfonamides with Alcohols by Ramachandran et al.a

a


Hence, due to the interest in oxidizing amines to imines (analogously to alcohols) by a transition metal complex, a few reactions involving transfer hydrogenation processes with amines233−236 and related reactions such as racemization of amines237 soon appeared in the literature. In parallel, research studies showed that alkyl amines could also participate in BH processes for forming imines and/or iminium cations, so that they may undergo analogous reactions to aldehydes and ketones as it will be shown. 2.3.1. Formation of C−C Bonds. 2.3.1.1. α-Alkylation. Cho et al. reported the α-alkylation of ketones with trialkylamines as hydrogen donors,238 in which the alkyl group was transferred by the in situ prepared catalyst of ruthenium (RuCl3 and PPh3) to give the final product. From these results, a variety of amines and ketones were reacted with this catalytic system. The reaction might take place

a

Adapted with permission from ref 190. Copyright 2015 Royal Society of Chemistry. Reaction conditions: 2.00 mmol of sulphonamides, 2.00 mmol of alcohol, KOH (50 mol %), catalyst (0.5 mol %) in 2 mL of toluene at 120 °C. bYields were calculated after isolation of the pure N-alkylated amine through column chromatography using silica gel (100−200 mesh).

presumably through an iminium intermediate that would react with the enolate derived from the ketone. The release of a secondary amine would lead to the alkylated ketone. This ruthenium-catalyzed reaction was regioselective and constituted the first example of alkyl-group transfer from trialkylamines (and imines) to the α-carbon atom of ketones. Later on, the same group reported the regioselective alkyl moiety transfer from a primary amine (82b) to a ketone (12a), following this procedure (Scheme 49).239 1433


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Scheme 46. Synthesis of Amine 82a by Borrowing Hydrogen Methodology through in Situ Sulfonamide Deprotectiona

a


Scheme 49. α-Alkylation of Acetophenone with Hexylamine Catalyzed by a Ru Complexa

Scheme 47. Ru Catalyzed Benzodiazepine Derivatives (93) Synthesis Reported by Taddei et ala

a a



Scheme 50. Primary Amine Alkylation Using Amines as Hydrogen Donors in BH Processes

This new contribution has the advantage of allowing access to the same products obtained with trialkylamines but generating ammonia instead of secondary amines as byproducts. The reaction pathway may undergo an analogous mechanism to that observed for alkyl transfer reactions with two different amines (see the following section 2.3.2.1).240 2.3.2. Formation of C−N Bonds. 2.3.2.1. Condensation. 2.3.2.1.a. N-Alkylation of Amines. In close analogy to the Nalkylation of amines with alcohols (see section 2.2.2.2.b), amines are also suitable candidates for being dehydrogenated in a first reaction step. In this case, the metal catalyzes the oxidative dehydrogenation of the starting amine to give a new imine electrophile, which immediately reacts with a second amine molecule to form an unstable aminoaminal intermediate. The latter extrudes ammonia to form a new imine intermediate that is subsequently hydrogenated by the metal hydrides leading to the alkylated final amine (Scheme 50). One of the numerous homogeneous catalysts reported for activating amines as hydrogen donors was described by Hollmann et al.241 In this case, the reaction was carried out in the presence of the Shvo catalyst. In this case, a compilation of aniline derivatives and primary amines reacted smoothly to provide the corresponding aromatic amines in excellent yields. It is worth mentioning the ability of iridium catalyst [e.g., {Cp*IrCl2}2 and alanine triazole iridium(III) complex],242,243

to couple two amines with excellent selectivity, even in the absence of bases. Indeed, amazingly even though both amines were exposed to undergo oxidation to the respective imine, only one of them behaved as a hydrogen source.242 For instance, one recent example described the crosscoupling of an alkyl amine and an aromatic amine using hydrogen autotransfer methodology. The catalyst was an alanine triazole iridium catalyst which efficiently promoted the C−N bond formation by reacting two different types of amines (Figure 6).243 Once the best catalytic conditions were identified, the BH method for forming amines was tested by using triethylamines as alkylating agent and the above-mentioned iridium catalyst. In

Scheme 48. Plausible Reaction Scheme for the Benzodiazepine Synthesisa

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Table 10. Results of the Catalyzed Amination of Aniline with Hexylamine with Different Co(II) Catalysts and Different Experimental Conditionsa Figure 6. Alanine triazole compound (ATAs) (141) coordinatively bonded to IrCl3 compound used as catalyst. Adapted with permission from ref 243. Copyright 2016 Elsevier.

this case, a wide range of functional groups was tolerated at different positions (methoxy, methyl, chloro, tert-butyl, etc.). The corresponding amines were obtained from moderate-togood yields. Alternatively, an interesting application of this strategy consisted of the catalytic α,β-H/D-exchange for tertiary amines in the presence of the Shvo’s catalyst studied by the Beller’s group.244 This is the only study reported so far based on this particular strategy to accomplish the α,β-H/D exchange. As has been highlighted previously, the replacement of classic ruthenium and iridium complexes by less expensive earth abundant elements is a major goal in synthetic chemistry. This has materialized in this case by using cobalt complexes in recent examples to synthesize amines. In this regard, it is interesting to remark a recent contribution by Yin and co-workers.245 This group reported for the first time a series of cobalt pincer complexes (142−147) able to efficiently catalyze the synthesis of a broad range of aromatic, aliphatic, and cyclic sec-amines, with amines as starting materials. These Co-complexes showed similar activities to those which were observed with previous Ir and Ru complexes (Figure 7).245

entry

catalyst

solvent

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12c 13d

1 2 3 4 5 6 2 2 2 2 2 2

toluene toluene toluene toluene toluene toluene toluene THF hexane benzene 1,4-dioxane toluene toluene

0 98 86 95:5 dr. The racemic alcohol (175) is oxidized by a Ru-pincer (173) complex to form a Ru-hydride and a ketone (176). The ketone would undergo condensation with the sulfonamide (174) to form the sulfinylimine (177). Finally, hydrogenation of the latter by the Ru-hydride complex would efficiently occur for

amines has also been addressed giving interesting optically active β-amino alcohols with high yields (76%) and moderate enantiomeric excess (77%). In the model reaction, 1,2-diols (165) will react with secondary amines (166) in the presence of a ruthenium catalyst coordinated to a chiral phosphine JOSIPHOS ligand (Scheme 59).265 In a much simpler example, the enantioselective amination of alcohols (168) with aromatic amines (169) for the synthesis of chiral amines (170) has been reported in the literature. In this case, diverse transition metal complexes formed by coordination with chiral ligands of preference for asymmetric hydrogenations were studied in combination with chiral Brönsted acids.266 Table 12 shows the results obtained with a set of alcohol substrates and one iridium complex (171) and a chiral phosphoric acid (172). 1439


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accessing the α-chiral sulfinylamine (178) with high diastereoselectivity (Scheme 60).267

3.1. Activation of Alkanes

3.1.1. Formation of C−C Bonds. 3.1.1.1. Olefin Metathesis. As previously stated in the section 2.1, alkane activation has been a target for research in the last century and is even more important today due to the finding of valuable reserves of natural gas.270 At the same time, the olefin metathesis, a reaction which has been receiving increasing attention since its discovery, has led to the implementation of relevant industrial procedures such as the Lummus ABB process, which converts the ethylene into propylene using heterogeneous catalysts.271 Taking into account these precedents, the BH methodology allowed the combination of both processes toward the transformation of a specific alkane into its higher and lower counterparts as previously shown in section 2.1. This fact triggered intensive research on the set up of heterogeneous catalytic systems, leading to the discovery of one of the first industrial alkane metathesis processes.272−274 In general, the BH heterogeneous version follows the same reaction steps described with homogeneous catalysts (section 2.1), hence involving the dehydrogenation of the initial alkane into an alkene (179), followed by metathesis of the alkene and hydrogenation of the metathesis product (180) to yield a new alkane (181) (Scheme 61).26,275

Scheme 60. Mechanism for the Hydrogen Borrowing via a Ruthenium(II) Pincer Complex (Ru-MACHO). Reproduced from ref 267. Copyright 2014 American Chemical Society

Scheme 61. Alkane Metathesis via Transfer HydrogenationOlefin Metathesisa

One of the most interesting conclusions drawn from this section is that most of the enantioselective processes are still unapproachable through BH methodology because there are still high barrier processes to induce some kind of enantioselection. This justifies the scarce number of examples that have appeared in the literature on the topic. Thus, in the short/medium term there is a need for new catalysts that help to overcome this energy limitation. From another perspective, research into the synthesis of new chiral primary amines (from racemic alcohols and ammonia), enantiopure amines (through amination of racemic amines), or asymmetric functionalization of the β-position via enamines remain as the three main goals that should be undertaken.

a

Adapted with permission from ref 26. Copyright 2006 AAAS.

For doing this, a combination of a dehydrogenation/ hydrogenation catalysts, for instance Pt/Al2O3, and a metathesis catalyst such as WO3 on silica was devised. Unfortunately, the dehydrogenation step was thermodynamically disfavored at low temperatures, and consequently, a temperature of 400 °C was required to get a high concentration of the olefin. Similarly, a different dual catalytic system was developed using a partially heterogeneous catalytic system consisting of Re2O7/Al2O3 and different homogeneous iridium catalysts (1, 2, 3, 182−185) deposited on γ-Al2O3 (Figure 8). The resulting catalysts were active in the metathesis of n-decane.276

3. BORROWING HYDROGEN METHODOLOGY IN HETEROGENEOUS CATALYSTS Heterogeneous catalysis through BH methodology slowly started to develop driven by the advances in homogeneous catalysis. However, in recent years it seems that heterogeneous catalysis is starting to take off. Indeed, the progress in designing heterogeneous catalysts for a sustainable synthesis in autotransfer processes is a growing area of research due to the advantages in terms of efficiency and sustainability. In this context, a variety of approaches going from the most simple and classic processes to the most novel and original ones for separating, recovering, and recycling heterogeneous catalysts have been reported in BH transformations.268,269 In this section, we will summarize recent examples on the straightforward synthesis of chemicals by the BH methodology with heterogeneous catalysts that will complement two previous microreviews.9,12 We will describe new examples according to the classification of this review. Exceptionally in the absence of new references, we will describe examples included in previous revisions so that readers do not miss out on the wide variety of different intermediate reactions catalyzed by heterogeneous catalysts (especially on the issue of activation of alcohols).

Figure 8. Iridium complexes 1, 2, 3, 182−185 deposited onto γ-Al2O3. Adapted with permission from ref 276. Copyright 2010 Wiley-VCH. 1440


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Scheme 62. Examples of Ta and W Complexes (186 and 188) Active for Alkane Metathesis and Their Heterogeneous Counterparts on SiO2 and Al2O3 (187 and 189)a

a

Adapted with permission from ref 279. Copyright 1999 Elsevier B.V. Adapted with permission from ref 287. Copyright 2005 Wiley-VCH.

Interestingly, the metathesis of n-decane by supported Ir(C2H4)/Al2O3 and Re2O7/Al2O3 [(molar ratio Ir:Re(1:2.5)] afforded a different distribution of alkanes.276 Furthermore, the strong adsorption of the iridium pincer catalysts on γ-alumina apparently prevented the unfavorable interaction between the iridium species and Re2O7 responsible for decomposition. Basset et al. reported a set of single site tantalum277−286 or tungsten-derived heterogeneous catalysts287,288 active for this reaction. Examples of some these grafted complexes (186−189) are displayed in the following scheme (Scheme 62).279,287 In this case, the alkane metathesis was conceived by using a single metal catalyst with dual activity (e.g., tantalum or tungsten).289−297 Therefore, the active site would have all the required properties to complete the whole process. That is C− H activation, dehydrogenation, hydrogenation, and metathesis. These results were complemented by studies on the reaction mechanism by supported tantalum hydride complexes.298−300 In this regard, an interesting recent study by Basset et al. reported the influence of the support on the metathesis reaction of n-decane in the presence of WMe5 on silica− alumina.301 Indeed the importance of the metathesis catalyzed by tungsten systems has been reinforced by the expansion of this reaction in different hydrocarbon valorizations.302 In this line, the same group reported a highly efficient molybdenium imido complex (190) as precatalyst for alkane metathesis as well as a molybdenum/imido neopentyl (Np) neopentylidene (191) catalyst, both of them supported on silica (Figure 9).303,304

A fact that highlights the importance of this reaction is the number of patents and academic reports that have been published for manufacturing alkanes using alkane metathesis as well as the preparation of supported organometallic compounds as catalysts.305−307 In parallel, efforts have also focused on bifunctional catalysts on which the synergy between a supported bimetallic Zr/W catalyst has been studied taking the metathesis reaction of ndecane as a model reaction.308 In this line, Zr-polyhydrides supported on SiO2 or SiO2/Al2O3 were also able to convert propane into lower and higher homologues, with 2-methylpropane being the major product.309 Besides this, tantalum hydrides were also examined. For example, the Schrock tantalum alkylidene Ta(CHCMe3)(CH2CMe3)3 was grafted onto partially dehydroxylated silica to generate a mixture of grafted complexes.310 Besides, the synthesis and characterization of a Ta−H supported on tetrahedral Zr(OH)4 was also accomplished [TaHx/ZrO2−SiO2].311 With this catalyst, a much better reactivity and selectivity values were obtained for the alkane metathesis with respect to the original TaHx/SiO2. For example, for the propane metathesis, the observed TON was 100 with [TaHx/ZrO2−SiO2] as catalyst compared to 58 for TaHx/SiO2 at 150 °C after 120 h. The improved activity of [TaHx/ZrO2−SiO2] was attributed to its slower deactivation rate. Different supports for Ta-polyhydrides such as SiO2/Al2O3 and Al2O3 were also employed as supports; although this time, similar results to those obtained with Ta−H/SiO2 were achieved for the metathesis of propane in terms of activity and selectivity. This behavior contrasts sharply with the ZrO2− SiO2 system, which has a tetrahedral Zr atom that separates the tantalum center from the coordinating surface oxygens. Other related supported hydrides such as WHx/SiO2 were found to be less active for alkane metathesis than TaHx/SiO2. The grafting of a Schrock precursor on alumina or silica/ alumina was also studied leading to more stable supported polyhydrides [WHx/SiO2−Al2O3] and [WHx/Al2O3].288,312 In close connection to the tungstene hydrides, the preparation of silica supported W-neopentylidene, alumina supported W-carbyne complexes, as well as silica supported WMe6 were reported.313−316 3.2. Activation of Alcohols

Figure 9. Structure of the molybdenum catalysts for alkane metathesis. Adapted with permission from ref 303. Copyright 2006 Wiley-VCH. Adapted with permission from ref 304. Copyright 2008 Wiley-VCH.

A compilation of heterogeneous C−C and C−N forming reactions through BH methodology using different intermedi1441


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Scheme 63. Preparation of Solid Metal Nanoparticles of Pd Starting form PdCl2 and the Non-Cross-Linked Viologen Polymera

a


interesting results obtained with Ni-based supported catalysts as well as different bases and reaction conditions. It is necessary to highlight an interesting result reported in the patent literature when palladium was supported on hydrotalcite derivatives (Pd/HT) and was used as catalysts for the Guerbet reaction. In particular, higher yields of nbutanol could be obtained when gallium was incorporated into the hydrotalcite structure. Besides, it was possible to carry out the process at lower temperatures.319,320 In a recent and interesting approach, the preparation of a DMF-stabilized iridium nanocluster as methylation catalyst has been described. The corresponding micrographs of HR-TEM showed that the small Ir clusters had an average diameter of 1− 1.5 nm and were stabilized with DMF.321 The characterization studies showed that DMF protected the Ir metal particles so that they started to have a weight loss at around 100 °C. Upon heating, it appears that a part of the protective DMF molecules were released, generating Ir nanoclusters with partially open sites that could act as active catalysts in the methylation reaction. The stabilized metal nanoclusters were used as catalyst in the β-methylation (196−197) of alcohols with methanol (26a). The following table (Table 14) shows the screening of the reaction conditions.321 Onyestyak et al. reported two closely related studies on the α-alkylation of acetone with ethanol in vapor phase using a fixed-bed reactor and two metal-based catalysts with a great potential for achieving C-alkylations, such as Pd and Cu.322,323 In both cases, the authors moved from batch to a flowthrough system trying to get closer to the systems that are most frequently used in the industry. Although a priori these results are not easy to compare with those obtained in batch, the authors reached promising results. In one of these studies,322 a basic hydrotalcite support (HT) was used instead of the typically inert carbon in an attempt to avoid the use of bases. Then Pd was deposited onto this basic solid as a dehydrogenation/hydrogenation catalyst. The reaction model was the αalkylation of acetone with different alcohols. They found that the initial reaction rates were much higher with Pd than with Cu. Moreover, Pd/HT was highly efficient in the alkylating reaction both under inert atmosphere and under H2. Besides, the selectivity and overall yield obtained with Pd were superior even when both metals were deposited on the basic carrier hydrotalcite HT (Pd 5 wt % and Cu 9 wt %). The same group described the upgrading of biofuel derived from an alcohol-acetone feedstock, and again this study was carried out over a two-stage flow through catalytic system.324 Finally, examples of bimetallic catalysts should also be highlighted as they have also been described in recent studies on cross-coupling reactions of primary and secondary alcohols under BH conditions. For example, Cu−Ag/hydrotalcite has been applied as a catalyst for dehydrogenative cross-coupling of

ate reactions such as aldol condensation, C3-alkylations, and Knoevenagel reactions among others have been described in specific literature revisions dealing with heterogeneous catalysis, albeit classified according to the type of global reaction.9,11 Therefore, continuing with our classification, we will focus on the intermediate characteristic reaction in tandem with BH dehydrogenation/hydrogenation using alcohols as hydrogen source. 3.2.1. Formation of C−C Bonds. 3.2.1.1. Aldol Condensation. Uozumi described a palladium nanocatalyst, composed of a mixture of palladium nanoparticles and a viologen polymer317 (194), in combination with barium hydroxide (Ba(OH)2), as a base for the α-alkylation of ketones. The Pd polymeric-based catalyst was prepared via a selforganization process of inorganic compounds and the noncross-linked viologen polymer. In particular, anionic species [PdX4]2− containing Pd self-assembled with the non-crosslinked cationic polymer (192) to give an ionic insoluble polymeric complex (193) which was reduced to afford nanoparticulated metal particles (Scheme 63).317 The solid catalyst 194 was characterized and applied to the α-alkylation of diverse ketones (12a−j) with alcohols under atmospheric conditions without using classic organic solvents (Scheme 64).317 Scheme 64. Examples of α-Alkylation of Ketones with Alcohols in the Presence of Nano-Pd-V catalysta

a

Adapted with permission from ref 317. Copyright 2007 Elsevier Ltd.

The reactions proceed under mild conditions to afford moderate yields of the respective alkylated ketones (20a−j). The solid could be easily recovered and recycled to meet with the requirments of green chemistry. Interestingly, the same palladium catalyst was applied in the ring opening of cyclic diketones.317 Nickel, rhodium, and ruthenium deposited on diverse supports were also effective catalysts for the Guerbet reaction between CH3OH and n-PrOH with complete selectivity toward the synthesis of isobutanol (iBuOH). Besides, the presence of sodium methoxide as a basic component was necessary in this case to get catalytic activity.318 Table 13 includes the most 1442


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Table 13. Results Obtained on the Guerbet Reaction by Reacting Methanol and Propanol with Different Nickel-Supported Catalysts and Basesa Ni-catalystb

basic component

iBuOH

entry

type

mmol

type

mmol

B/Ni

time (h)

T (°C)

PH2 (atm)

PN2 (atm)

yieldc (%)

TNd (h−1)

e

Ni/k Ni/k Ni/k Ni/k Ni/k Ni/k Ni/Al2O3 Ni/Al2O3 Ni/Al2O3 Ni/(OAc)2 NiCl2(PiPr3)2

2.56 2.56 2.56 0.97 0.20 0.20 0.45 0.20 0.20 0.125 0.098

MgO KOH MeONa MeONa MeONa MeONa MeONa MeONa MeONa MeONa MeONa

80 160 160 160 160 160 160 160 160 160 160

31 63 63 165 800 800 355 800 800 1280 1633

6 6 6 12 6 6 12 12 6 6 6

200 200 180 200 200 200 200 200 200 200 200

30 30 30 − − − − − − − −

− − − 30 30 30 30 30 30 30 30

0.8 1.3 20.0 55.3 49.5 48.0 48.8 25.5 41.0 31.3 38.6

0.05 0.08 1.30 9.50 41.2 40.0 18.1 21.1 34.2 41.7 65.6

1 2e 3e 4e 5e 6f 7e 8e 9f 10f 11f a

Adapted with permission from ref 318. Copyright 2003 Elsevier. Reaction conditions: MeOH (1250 mmol); MeOH/PrOH (12.5 mol/mol). bNi/k represents a commercial catalyst (G49 from Girdler) containing 5 wt % of nickel on kieselguhr, whereas Ni/Al2O3 represents a commercial catalyst (3288 from Engelhard) containing 60 wt % of nickel on alumina. cCalculated with respect to PrOH. dTurnover number calculated after 6 h of reaction and expressed as mol iBuOH/(mol Ni × h). ePreactivated nickel catalysts were used. fNo preactivation of the metal catalyst was performed.

Table 14. Screening of the Reaction Conditionsa

entry 1 2 3e 4e 5e,f 6e 7 8 9 10 11 12 13g 14h 15h,i

[Ir] Ir NCs IrCl3 IrCl3 [IrCl(cod)]2 [IrCl(cod)]2/ PPh3 [Cp*IrCl2]2 Ir NCs Ir NCs Ir NCs Ir NCs none none Ir NCs Ir NCs Ir NCs

between benzyl alcohol (13a) and phenylacetonitrile (199), or diethylmalonate (203) or nitromethane, to give the respective α-monoakylated products (201, 204, and 206) without external supply of hydrogen. The process involved a three-step process taking place on two different catalytic surface sites. First, the alcohol was oxidized to the corresponding aldehyde (198) with the simultaneous formation of a metal hydride, and then the aldehyde reacted with a methylene activated compound to give an alkene (200, 202, and 205), and finally hydrogen from the metal hydride was transferred to the alkene to give a new saturated C−C bond (Scheme 65).327 Kinetic studies showed that the rate-controlling step for the one-pot reaction sequence between benzylacetonitrile and benzyl alcohol was the hydrogen transfer reaction from the surface hydrides to the olefin, and more importantly, the global reaction rate improved when decreasing the size of the Pd metal nanoparticle (Scheme 65). The alkylation of heterocyclic compounds with hydroxyl compounds has been also attempted recently with Pd/C and Ru/C.104,320 The importance of this reaction relies on the fact that heterocyclic compounds are relevant structural motifs in molecules of biological and pharmaceutical importance (barbiturates, coumarins, etc.). Since such alkylated heterocyclic compounds are intermediates for the synthesis of useful molecules, the development of green and selective methods for alkylating heterocycles is a key matter in synthetic chemistry. For example, commercially available Pd/C was active in the alkylation of 4-hydroxycoumarin, 4-hydroxy-1methylquinoline, and barbituric and oxoindole derivatives. The alkylation (208) of 1,3-dimethylbarbituric acid (207) was successfully scaled-up to one gram. Furthermore, the catalyst could be recycled up to five times with a negligible loss of efficiency (Figure 10).320 3.2.2. Formation of C−N Bonds. 3.2.2.1. Aza-Wittig Reaction. Yus et al. reported in 2008 the Aza-Wittig reaction between different alcohols (13a) and N(triphenylphosphoranilidene)aniline (209) in the presence of Ni nanoparticles.328 The reaction was carried out in the absence of a base and under mild conditions. The main drawbacks were the moderate yields to the corresponding secondary amines (68a) and the amount of catalyst used (Scheme 66).328

total yieldb,c [%] selectivity (196:197)d

base

Conv. (26a) [%]

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

>99 48 49 48 44

68 16 16 21 18

Cs2CO3 KOH KOtBu K2CO3 none Cs2CO3 KOH Cs2CO3 Cs2CO3 Cs2CO3

44 >99 >99 59 26 30 60 11 >99 57

25 (25:75) 53 (87:13) 52 (87:13) 31 (75:25) n.d. n.d. 9 (>99: −) 3 (48:52) quant [87]c (94:6) 24 (94:6)

(85:15) (46:54) (33:67) (28:72) (−: >99)

a

Adapted with permission from ref 321. Copyright 2017 Royal Society of Chemistry. Reaction conditions: 26a (1 mmol) was allowed to react with methanol (2 mL), redissolved Ir NCs (0.1 mol %) and Cs2CO3 (1 mmol) at 150 °C for 24 h. bGC yields based on 26a used. cThree numbers in the square bracket show isolated yields. dThe numbers in parentheses show the selectivity for the alcohol and ketone products. e Ir catalyst (5 mol %) was used. fPPh3 (10 mol %) was used. gAt 100 °C. hCs2CO3 (3 mmol) was used. iIr NCs (0.001 mol %) for 48 h.

primary and secondary benzylic alcohols.325 Besides, Pt−Sn deposited onto γ-Al2O3 catalyzed the β-alkylation of secondary alcohols with primary alcohols under solvent-free conditions.326 3.2.1.2. Knoevenagel Reaction. There are few examples on the Knoevenagel reaction as intermediate reaction in BH methodology using heterogeneous catalysts. One of them has to do with monoalkylation reactions of diverse C−H acid methylene compounds in the presence of a bifunctional metalbased catalyst.327 In particular, Pd supported on basic MgO of high surface area (Pd/MgO) catalyzed the sequential reaction 1443


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Scheme 65. Schematic Representation of the αMonoalkylation Reaction of Phenylacetonitrile, Diethylmalonate, and Nitromethane with Benzyl Alcohol over Pd/MgOa

a

reaction in the presence of a heterogeneous catalyst. To the best of our knowledge, there are no further publications reporting improvements in this field. 3.2.2.2. Condensation. 3.2.2.2.a. N-Alkylation of Ammonia (Amination of Alcohols with Ammonia). The incorporation of ammonia as a nucleophile in the amination of alcohols is a long-standing goal when it comes to heterogeneous catalysis, as it happened with the homogeneous counterpart. In this context, experimental parameters such as the ammonia pressure and reaction temperature will significantly vary depending on the catalyst and the type of substrate. For example, methanol and ammonia will react together at 350−500 °C and 15−30 bar using aluminum-based heterogeneous catalysts in determined industrial processes.329 It can be noticed that most heterogeneous catalysts active in amination of alcohols contain mainly tungsten, copper, iron, cobalt, nickel, and chromium as metallic elements, whereas it is known that the product distribution can be tuned by changing parameters such as the residence time and excess of ammonia. In particular, using the catalytic BH strategy, it has been recently shown that small nickel nanoparticles supported on calcium silicate (CaSiO3) by ion exchange followed hydrogenation of the calcined material afforded a Ni/CaSiO3 material with high activity in the obtention of primary amines from NH3 and alcohols. In this case, the catalytic active species is the metallic Ni(0) sites of about 3 nm particle size. It is important to indicate that the solid system was active in the alkylation of anilines as well as aliphatic amines with alcohols (aliphatic and benzyl alcohols) under neat conditions.330 One of the most recent examples of alkylation of ammonia using heterogeneous catalysts has to do with the amination of diverse biogenic isohexides which has been carried out with Ru/C in aqueous phase (Scheme 67).331


Scheme 67. Amination of Isohexides Yields Four Amino Alcohols and Three Diamines with Different Configuration (Endo/Exo) of the Hydroxyl and Amine Groups in Positions 2 and 5a

Figure 10. Graphic representation of the recycling of Pd/C by reacting the barbituric derivative 207 and alcohol 13a. Adapted with permission from ref 320. Copyright 2015 Wiley-VCH.

a

Scheme 66. Indirect Aza-Wittig Reaction Catalyzed by NiNPsa

Isohexides are biogenic substrates that dissolve well only in polar solvents. For this reason, the amination of these molecules with alcohols was carried out in aqueous phase. The reaction was catalyzed with Ru/C in aqueous ammonia and using low pressures of H2. The importance of this reaction relies in the fact that the catalyst is active in the transformation of secondary alcohols toward primary amines (210−216) in water through BH catalysis. This fact is striking if we take into account that water in principle would shift the equilibrium of the imine formation toward the nonfavored ketone so that the formation of amine would not be favored.

a


This is the first example reported in the literature on the activation of an alcohol to carry out the indirect aza-Wittig 1444



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catalysts.339 In this context, several examples of industrial applications carried out with such amination processes have been described to take place in the presence of different heterogeneous catalysts (e.g., the N-alkylation of lower aliphatic amines with CH3OH). In accordance to this, descriptions of these processes can be found with relative frequency in the patent literature.329,340,341 However, despite the fact that the amination of alcohols is a reaction of reference within the context of borrowing hydrogen, there is not a general catalytic method available for functionalized and/or sensitive or unstable compounds under milder reaction conditions (T < 100 °C). The problem has been temporarily solved in some cases by switching from heterogeneous to homogeneous phase working with organometallic catalysts (e.g., by immobilizing iridium complexes on siliceous supports),342 albeit the search of more active solid catalysts has not stopped ever. A very interesting contribution related to gold and silver nanoparticles as metal catalysts has to do with the reductive Nalkylation of nitroarenes using borrowing hydrogen methods.343,344 As an example, with the proper reaction conditions small gold nanoparticles (1.8 nm) deposited on TiO2 (Au/TiO2) were very active for the N-monoalkylation reaction or dialkylation of nitroarenes (5, 5a) with alcohols (13, 13a). The reaction involved the dehydrogenation reaction of the alcohol to form the aldehyde and concurrently the reduction of the nitroarene to give the respective amine (220, 221). Notably other functional groups susceptible to be reduced, such as alkenes, ketones, or esters moieties, remained unreacted during the reductive N-monoalkylation reaction (Scheme 69).343

The synthesis of dodecylamine from dodecanol and ammonia has been recently reported to occur in the presence of metals such as platinum, palladium, ruthenium, iridium, and osmium supported on carbon. Interestingly, the authors found that the presence of an extra supply of hydrogen gas was beneficial to reach a high conversion as well as a high dodecylamine selectivity.332 As it has been already shown in the previous section devoted to homogeneous catalysis, ammonia has been successfully replaced in numerous examples by other alternative chemical sources, and these concerns have also reached to heterogeneous catalysis. In this case, one of the first examples reported by the group of Mizuno studied the synthesis of both secondary and tertiary amines (218, 219) from alcohols (13a, 26a) and urea (217), albeit this time in the presence of a recoverable heterogeneous ruthenium catalyst.333 The relatively wide scope of this catalytic system was evidenced by the transformation of primary alcohols into tertiary amines, whereas other more hindered alcohols (secondary alcohols) were converted into secondary amines (Scheme 68)333 in both cases using an alcohol excess. Scheme 68. Supported Ru(OH)x Catalyzed Formation of Secondary and Tertiary Amines from Benzylic Alcohols and Ureaa

Scheme 69. Au/TiO2-Catalyzed Reaction of Nitroarenes with Benzyl Alcohols and Nitrobenzene with Various Alcohols via BH Methodologya a


Another interesting approach studied the use of aqueous ammonia as an alternative to the need of a pressure equipment because of the ease of handling. From these results, it follows that the importance of primary amines both by themselves and as intermediates for further derivatization reactions pushed the researchers to undertake the development of efficient ways to prepare amines through BH methodology as an alternative to known classical synthetic procedures.334,335 So far, studies on bimetallic catalysts on this specific subject are scarce, albeit exceptionally the bibliography has described a bimetallic Rh−In/C catalyst which has been applied in aqueous medium with ammonia as the nucleophile for the amination of diverse C3 alcohols (e.g., 1,3-propanediol). Among the screened activated carbons, the use of FAC-10 must be highlighted as the best support in terms of activity and resistance to metal leaching, giving a Rh−In alloy particle size of 3−4 nm, according to the TEM micrographs.336 3.2.2.2.b. N-Alkylation of Primary and Secondary Amines with Alcohols. The use of solid catalysts for alcohol aminations is known from the first decades of the last century.337,338 Nonetheless, the interest in the N-alkylation of amines using heterogeneous catalysts through BH methods derives from the success in the preparation of homogeneous complexes as has been indicated in section 2.2.2.2.b dealing with homogeneous

a


The fact the Au−H complexes selectively reduce both the nitro group (as reactant) and the intermediate imine formed in situ to get another amine as final product shows the advantages of BH methodology for implementing intensive processes. Secondary amines have also been obtained from alcohols and nitroarenes in the presence of Pd deposited on a semiconductor TiO2 (Pd/TiO2) with the contribution of UV irradiation (λ ≥ 300 nm) and at room temperature (Scheme 70).345 Pd/TiO2 catalyzed the one-pot synthesis of secondary amines from alcohols and nitroarenes under UV light, with a combination of photocatalytic and catalytic reactions consisting of (i) photocatalytic oxidation of the starting alcohol to the corresponding aldehyde and reduction of nitroarenes to afford the respective aniline compound; (ii) then condensation reaction of the formed carbonyl compounds and anilines and, (iii) photocatalyzed hydrogenation of the formed imines to give secondary amines. 1445


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Scheme 70. Catalyst Properties and Results for One-Pot Synthesis of Secondary Amine from Nitrobenzene and Benzyl Alcohol under UV Irradiationa

a


via back spillover phenomenon between Pd and the ceria support, being regarded as the main driver for amination under the hydrogen borrowing mechanism. Other interesting material employed as support was cryptomelane-type manganese oxide octahedral molecular sieve (OMS-2), which was examined as a possible candidate for amination reactions. OMS-2 materials (also called Khollandites or γ-MnO2) are based on edge-shared MnO6 octahedra, having both Mn(III) and Mn(IV) cations, and 2 × 2 1D microtunnels, having extra framework compensation ions (usually K+).349 This K-hollandite was Pd-substituted by the cation-exchanged method showing activity for the straightforward amination of alcohols with primary amines.350 The model reaction using aniline and benzyl alcohol gave a N-benzylamine yield of 96% at 160 °C during 3 h with no formation of tertiary amine nor toluene. The good performance of this formulation was due to the formation of a highly active intermediate phase during the reaction which included the existence of a highly dispersed Pd(IV)/Pd(II) species near K and defective OH moieties, which favored the hydrogenation transfer. In order to expand the scope of reactions catalyzed by gold taking place in one-pot through the borrowing hydrogen strategy, a nanoparticulated gold catalyst on CeO2 (Au/CeO2) was able to integrate the N-monoalkylation of amines with an additional catalytic cycle to access more complex structures such as propargylamines.351 Indeed, Au/CeO2 connected two catalytic cycles in a gold-catalyzed cascade mode (Scheme 72).351

In principle, TiO2 would oxidize the alcohol, producing aldehyde and protons (H+). Then the photoexcited electrons would reduce H+ on the Pd particles giving to afford H−Pd species. These metal hydride species may reduce nitroarene to give aniline. Catalytic condensation of the formed aniline and aldehyde by the Lewis acid sites on the surface of TiO2 may produce the imine. This imine would be then hydrogenated by the H−Pd species to afford the corresponding amine. Meanwhile, the one pot reaction between nitrobenzene and diverse alcohols to afford secondary amines and imines has also been catalyzed by bimetallic nanoalloys of gold−palladium and ruthenium−palladium supported on titania.346 The metal-based catalysts were prepared by a modified impregation procedure. The authors found that bimetallic catalysts were far more active than the related monometallic ones due probably to a synergistic effect, following the order: Ru < Pd < Au ≪ Au− Pd < Ru−Pd. In this regard, another bimetallic catalyst formed by different elements Pt−Sn/γ-Al2O3 has also been reported recently to catalyze the scalable synthesis of secondary and tertiary amines from amines and alcohols.347 Pd supported on CeO2 (Pd/CeO2) has been reported to behave as a reservoir and H2-pump for the direct amination of alcohols (Scheme 71).348 Scheme 71. Hydrogen Transfer Pathway over Pd/CeO2−HS for the Amination of Benzyl Alcohol with Aniline (And Ammonia)a

Scheme 72. Two Multistep Catalytic Cycles for the One-Pot Synthesis of Propargylamines from Primary Amines and Alcohols with Au/CeO2: Cycle A = N-Monoalkylation; Cycle B: A3 Coupling Reactiona

a


In the first cycle (A, Scheme 72), gold atoms at the crystal corners promoted the N-monoalkylation of amines (82) with alcohols (195) to afford secondary amines (222) under hydrogenation transfer conditions. Then in a consecutive cycle (B, Scheme 72) 2-propinylamines (223) were formed through a multicomponent A3 transformation, involving alkynes (11) and aldehydes, extending the applicability of Au/CeO2 catalyst.351 The strategy led to the direct formation of C−C and C−N bonds through different consecutive transformations without interferences, a feature that resulted in a more intensive process

a

For the sake of clarity, only a CeO2(111) plane is represented. Adapted with permission from ref 348. Copyright 2016 Wiley-VCH.

In this case, a high surface CeO2 material was pretreated at 500 °C, resulting in an abnormally highly active and selective catalyst for the N-monoalkylation of benzyl alcohol with ammonia and primary amines such as aniline as compared to the standard Pd/CeO2 catalyst. In this case, a promoted H2 transfer on high-surface Pd/CeO2 was proposed to take place 1446


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in the presence of Pd supported on a basic support (Pd/ MgO).353 Effectively, bifunctional palladium-based catalyst (Pd/MgO) was able to form thioethers starting from thiols and aldehydes formed previously in situ from the respective alcohol under BH conditions. The reaction begun with a dehydrogenation of the alcohol (13a) to afford a palladium hydride intermediate and an aldehyde. The latter reacted with a thiol (224) involving most probably the intermediacy of a hemithioacetal (225) and a thionium ion RCH = S+R, being reduced in situ by the metal hydrides to afford thioethers (226a) (Scheme 74).353 The reaction is a variation of the reductive thiolation of aldehydes by Pd−H species, in which both reactants were formed and reacted in situ on the metal surface to give thioethers. The reaction is general for thiols (224) as well as benzylic alcohols (13a), affording disulfides (227) along with the desired thioethers (226a−d) (Scheme 75).353

and higher product yield. In this case, because two different oxidation states of gold (Au0 for the N-monoalkylation reaction and Au+n for the A3coupling) catalyzed two different reactions, the experimental conditions (temperature, metal loading, and preparation of catalyst) had to be optimized to avoid a sharp decrease of these oxidized gold active species as well as their sinterization. The strong interaction between different gold species on CeO2 accounted for the observed high activity and stability of the catalytic species during the overall cascade reaction.351 3.2.2.2.c. N-Alkylation of Amides and Sulfonamides with Alcohols. Recently it has been described a synergistic cascade reaction catalyzed by Lewis acids and supported bimetallic Au/ Pd as example of BH strategy352 in the N-alkylation of amides (Scheme 73).352 Scheme 73. N-Alkylation of Primary Amides with Alcohols via Hydrogen Autotransfer in the Presence of a Dual Catalysta

3.3. Activation of Amines

3.3.1. Formation of C−N Bonds. 3.3.1.1. Condensation (N-Alkylation). The alkylation reaction of amines with amines is a well-known reaction. Diverse heterogeneous active catalysts were described in the literature a long time ago for the Nalkylation of amines with themselves acting as electrophiles analogously to alcohol molecules. For example, the synthesis of symmetrically substituted secondary amines was successfully carried out via the Cu/Al2O3 catalyzed self-condensation of primary amines.354 Here diverse copper catalysts were screened for their activity in the self-coupling of the benzylamine as a model reaction against a series of different metal-loaded catalysts (e.g., Pd/Al2O3, Ru/Al2O3, and AgAl2O3). The following table (Table 15) includes some of the most significant results (228−231).354 Mechanistic studies were also carried out, and on the bases of different experimental observations the authors concluded that the reaction proceeded with the intervention of an intermediate Cu−H specie. This hydride species was formed after the initial dehydrogenation step, whereas hydrogen apparently was stored on the support through some kind of spillover effect. γ-Alumina or similar related phases were the most effective supports over the rest of the supports essayed.354 In a second example, a similar self-autocondensation of primary amines took place to give secondary amines using the same copper-based catalyst Cu/Al2O3, which was in turn

a

Adapted from ref 352. This article is licensed under a Creative Commons Attribution 3.0 Unported License.

3.2.3. Formation of C−S Bonds. 3.2.3.1. Thioetheri®cation (S-Alkylation). Formation of C−S bonds has also been exceptionally achieved with a heterogeneous catalyst by means of borrowing hydrogen methods by reacting thiols and alcohols

Scheme 74. Hypothetical Reaction Pathway for the One-Pot Synthesis of Thioethers with Pd/MgO Catalyst through a BH Strategya

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Scheme 75. Thioethers Obtained with This Methodologya

a


Table 15. Results on the Self N-Alkylation Reaction of Benzylamine in the Presence of Different Solid-Metal Catalystsa

yield (%) entry

catalyst

solvent

time (h)

228

229

230

231

1 2 3 4 5b 6c 7 8 9 10 11 12 13d 14 15 16 17 18 19 20 21 22 23 24 25 26d 27

Cu/Al2O3 Cu/Al2O3 Cu/Al2O3 Cu/Al2O3 Cu/Al2O3 Cu/Al2O3 Cu/TiO2 Cu/CeO2 Cu/SiO2 Cu(OH)x/Al2O3 CuCl2/Al2O3 (pretreated with H2 at 180 °C) Cu(OAc)2/Al2O3 (pretreated with H2 at 180 °C) Cu metal + Al2O3 CuO Cu(OH)2 Cu2O CuCl2·2H2O Cu(OAc)2·2H2O CuCl Ag/Al2O3 Au/Al2O3 Ru/Al2O3 Rh/Al2O3 Pd/Al2O3 Pt/Al2O3 Al2O3 None

mesitylene mesitylene diglyme o-dichlorobenzene DMSO DMF mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene

3 24 3 3 3 3 3 3 3 24 24 24 24 24 24 24 24 24 24 3 3 3 3 3 3 3 24

64 97 31

Advances in One-Pot Synthesis through Borrowing Hydrogen

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